Indolinone derivatives substituted in the 6 position, their preparation and their use as medicaments

ABSTRACT

The present invention relates to indolinone derivatives, substituted in the 6-position, of the formula 
     
       
         
         
             
             
         
       
     
     in which
 
R 1  to R 6  and X are as defined in Claim  1 , to their tautomers, enantiomers, diastereomers, to their mixtures and to their salts, in particular their physiologically acceptable salts, which have useful pharmacological properties, in particular in inhibiting action on various receptor tyrosine kinases and on the proliferation of endothelial cells and various tumour cells, to medicaments comprising these compounds, to their use and to processes for their preparation.

RELATED APPLICATIONS

This is a continuation of U.S. application Ser. No. 10/625,101 filed onJul. 22, 2003, which claims, as does the present application, prioritybenefit of U.S. Provisional Application Ser. No. 60/403,106, filed onAug. 13, 2002, DE 10233366.1 filed Jul. 23, 2002, and DE 10328533.4,filed Jun. 24, 2003 are hereby claimed, and said applications are hereinincorporated by reference.

The present invention relates to indolinone derivatives, substituted inthe 6-position, of the formula

to their tautomers, enantiomers, diastereomers, their mixtures and theirsalts, in particular their physiologically acceptable salts, which haveuseful pharmacological properties, to medicaments comprising thesecompounds to their use and to processes for their preparation.

The above compounds of the formula I have useful pharmacologicalproperties, in particular an inhibition action on various kinases,especially on receptor tyrosine kinases, such as VEGFR1, VEGFR2, VEGFR3,PDGFRα, PDGFRγ, FGFR1, FGFR3, EGFR, HER2, c-Kit, IGF1R and HGFR, Flt-3,and on the proliferation of cultivated human cells, in particular thatof endothelial cells, for example in angiogenesis, but also on theproliferation of other cells, in particular tumour cells.

Accordingly, the present invention provides the above compounds of theformula I, which have useful pharmacological properties, medicamentscomprising these pharmacologically active compounds, their use andprocesses for their preparation.

Moreover, the present invention provides the physiologically acceptablesalts of the compounds according to the invention, medicamentscomprising these compounds which in addition, if appropriate, containone or more inert carrier materials and/or diluents, and their use forpreparing a medicament suitable in particular for treating excessive oranormal cell proliferations.

The present invention furthermore provides processes for preparing thismedicament, characterized in particular in that the compounds accordingto the invention or their physiologically acceptable salts areincorporated into one or more inert carrier materials and/or diluents.

-   I. In the above formula I,    -   X is an oxygen atom,    -   R¹ is a hydrogen atom,    -   R² is a fluorine, chlorine or bromine atom or a cyano group,    -   R³ is a phenyl group or a phenyl group which is monosubstituted        by a fluorine, chlorine, bromine or iodine atom or by a        C₁₋₃-alkoxy group, where the abovementioned unsubstituted and        the monosubstituted phenyl groups may additionally be        substituted in the 3- or 4-position        -   by a fluorine, chlorine or bromine atom,        -   by a cyano group,        -   by a C₁₋₃-alkoxy or C₁₋₂-alkyl-carbonyl-amino group,        -   by a cyano-C₁₋₃-alkyl, carboxy-C₁₋₃-alkyl,            carboxy-C₁₋₄-alkoxy, carboxy-C₁₋₃-alkylamino,            carboxy-C₁₋₃-alkyl-N—(C₁₋₃-alkyl)-amino,            C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl,            C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkoxy,            C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkylamino,            C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl-N—(C₁₋₃-alkyl)-amino,            amino-C₁₋₃-alkyl, aminocarbonyl-C₁₋₃-alkyl,            (C₁₋₂-alkylamino)-carbonyl-C₁₋₃-alkyl,            di-(C₁₋₂-alkyl)-aminocarbonyl-C₁₋₃-alkyl,            (C₁₋₂-alkyl-carbonyl)-amino-C₁₋₃-alkyl,            (C₁₋₄-alkoxy-carbonyl)-amino-C₁₋₃-alkyl,            (C₃₋₆-alkyl-carbonyl)-amino-C₁₋₃-alkyl,            (phenyl-carbonyl)-amino-C₁₋₃-alkyl,            (C₃₋₆-cycloalkyl-carbonyl)-amino-C₁₋₃-alkyl,            (C₃₋₆-cycloalkyl-C₁₋₃-alkyl-carbonyl)-amino-C₁₋₃-alkyl,            (thiophen-2-yl-carbonyl)-amino-C₁₋₃-alkyl,            (furan-2-yl-carbonyl)-amino-C₁₋₃-alkyl,            (phenyl-C₁₋₃-alkyl-carbonyl)-amino-C₁₋₃-alkyl,            (2-(C₁₋₄-alkoxy)-benzoyl-carbonyl)-amino-C₁₋₃-alkyl,            (pyridin-2-yl-carbonyl)-amino-C₁₋₃-alkyl,            (pyridin-3-yl-carbonyl)-amino-C₁₋₃-alkyl-,            (pyridin-4-yl-carbonyl)-amino-C₁₋₃-alkyl- or            C₁₋₃-alkyl-piperazin-1-yl-carbonyl-C₁₋₃-alkyl group,        -   by a carboxy-C₂₋₃-alkenyl, aminocarbonyl-C₂₋₃-alkenyl,            (C₁₋₃-alkyl-amino)-carbonyl-C₂₋₃-alkenyl,            di-(C₁₋₃-alkyl)-amino-carbonyl-C₂₋₃-alkenyl or            C₁₋₄-alkoxy-carbonyl-C₂₋₃-alkenyl group,        -   where the substituents may be identical or different,    -   R⁴ is a phenyl group or a phenyl group which is monosubstituted        -   by a C₁₋₃-alkyl group which is terminally substituted by an            amino, guanidino, mono- or di-(C₁₋₂-alkyl)-amino-,            N—[ω-di-(C₁₋₃-alkyl)-amino-C₂₋₃-alkyl]-N—(C₁₋₃-alkyl)-amino,            N-methyl-(C₃₋₄-alkyl)-amino, N—(C₁₋₃-alkyl)-N-benzylamino,            N—(C₁₋₄-alkoxycarbonyl)-amino,            N—(C₁₋₄-alkoxycarbonyl)-C₁₋₄-alkylamino,            4-(C₁₋₃-alkyl)-piperazin-1-yl, imidazol-1-yl,            pyrrolidin-1-yl, azetidin-1-yl, morpholin-4-yl,            piperazin-1-yl, thiomorpholin-4-yl group,        -   by a di-(C₁₋₃-alkyl)-amino-(C₁₋₃-alkyl)-sulphonyl,            2-[di-(C₁₋₃-alkyl)-amino]-ethoxy,            4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl,            {ω-[di-(C₁₋₃-alkyl)-amino]-(C₂₋₃-alkyl)}-N—(C₁₋₃-alkyl)-amino-carbonyl,            1-(C₁₋₃-alkyl)imidazol-2-yl, (C₁₋₃-alkyl)-sulphonyl group,            or        -   by a group of the formula

-   -   -   in which            -   R⁷ is a C₁₋₂-alkyl, C₁₋₂-alkyl-carbonyl,                di-(C₁₋₂-alkyl)-amino-carbonyl-C₁₋₃-alkyl or                C₁₋₃-alkylsulphonyl group and            -   R⁸ is C₁₋₃-alkyl, ω-[di-(C₁₋₂-alkyl)-amino]-C₂₋₃-alkyl,                ω-[mono-(C₁₋₂-alkyl)-amino]-C₂₋₃-alkyl group, or            -   a (C₁₋₃-alkyl)-carbonyl, (C₄₋₆-alkyl)-carbonyl or                carbonyl-(C₁₋₃-alkyl) group which is terminally                substituted by a di-(C₁₋₂-alkyl)-amino, piperazin-1-yl                or 4-(C₁₋₃-alkyl)-piperazin-1-yl group,

    -   where all dialkylamino groups present in the radical R⁴ may also        be present in quaternized form, for example as an        N-methyl-(N,N-dialkyl)-ammonium group, where the counterion is        preferably selected from the group consisting of iodide,        chloride, bromide, methylsulphonate, para-toluenesulphonate and        trifluoroacetate,

    -   R⁵ is a hydrogen atom and

    -   R⁶ is a hydrogen atom,

    -   where the abovementioned alkyl groups include linear and        branched alkyl groups in which additionally one to 3 hydrogen        atoms may be replaced by fluorine atoms,

    -   where additionally a carboxyl, amino or imino group present may        be substituted by an in vivo cleavable radical or may be present        in the form of a prodrug radical, for example in the form of a        group which can be converted in vivo into a carboxyl group or in        the form of a group which can be converted in vivo into an imino        or amino group,

    -   their tautomers, enantiomers, diastereomers, their mixtures and        their salts.

-   II. Particularly preferred compounds of the above formula I are    those compounds in which X, R¹, R⁵ and R⁶ are as defined under I.    and:    -   II.i. R² and R⁴ are as defined under I. and    -   R³ is a phenyl group or a phenyl group which is monosubstituted        by a fluorine, chlorine, bromine or iodine atom or by a        C₁₋₃-alkoxy group, where the abovementioned unsubstituted and        the monosubstituted phenyl groups may additionally be        substituted in the 3- or 4-position        -   by a fluorine, chlorine or bromine atom,        -   by a cyano group,        -   by a C₁₋₃-alkoxy or C₁₋₂-alkyl-carbonyl-amino group,        -   by a cyano-C₁₋₃-alkyl, carboxy-C₁₋₃-alkyl,            carboxy-C₁₋₄-alkoxy, carboxy-C₁₋₃-alkylamino,            carboxy-C₁₋₃-alkyl-N—(C₁₋₃-alkyl)-amino,            C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl,            C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkoxy,            C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkylamino,            C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl-N—(C₁₋₃-alkyl)-amino,            amino-C₁₋₃-alkyl, aminocarbonyl-C₁₋₃-alkyl,            (C₁₋₂-alkylamino)-carbonyl-C₁₋₃-alkyl,            di-(C₁₋₂-alkyl)-aminocarbonyl-C₁₋₃-alkyl,            (C₁₋₂-alkyl-carbonyl)-amino-C₁₋₃-alkyl,            (C₁₋₄-alkoxy-carbonyl)-amino-C₁₋₃-alkyl,            (C₃₋₆-alkyl-carbonyl)-amino-C₁₋₃-alkyl,            (phenyl-carbonyl)-amino-C₁₋₃-alkyl,            (C₃₋₆-cycloalkyl-carbonyl)-amino-C₁₋₃-alkyl,            (C₃₋₆-cycloalkyl-C₁₋₃-alkyl-carbonyl)-amino-C₁₋₃-alkyl,            (thiophen-2-yl-carbonyl)-amino-C₁₋₃-alkyl,            (furan-2-yl-carbonyl)-amino-C₁₋₃-alkyl,            (phenyl-C₁₋₃-alkyl-carbonyl)-amino-C₁₋₃-alkyl,            (2-(C₁₋₄-alkoxy)-benzoyl-carbonyl)-amino-C₁₋₃-alkyl,            (pyridin-2-yl-carbonyl)-amino-C₁₋₃-alkyl,            (pyridin-3-yl-carbonyl)-amino-C₁₋₃-alkyl,            (pyridin-4-yl-carbonyl)-amino-C₁₋₃-alkyl or            C₁₋₃-alkyl-piperazin-1-yl-carbonyl-C₁₋₃-alkyl group,        -   by a carboxy-C₂₋₃-alkenyl, aminocarbonyl-C₂₋₃-alkenyl-,            (C₁₋₃-alkyl-amino)-carbonyl-C₂₋₃-alkenyl-,            di-(C₁₋₃-alkyl)-amino-carbonyl-C₂₋₃-alkenyl or            C₁₋₄-alkoxy-carbonyl-C₂₋₃-alkenyl group,        -   where the substituents may be identical or different;    -   II.ii. R² and R⁴ are as defined under I. and    -   R³ is a phenyl group which is substituted        -   by a C₁₋₂-alkyl-carbonyl-amino group, by a            carboxy-C₁₋₃-alkyl, carboxy-C₁₋₄-alkoxy,            C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl,            C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkoxy, aminocarbonyl-C₁₋₃-alkyl,            (C₁₋₂-alkylamino)-carbonyl-C₁₋₃-alkyl,            di-(C₁₋₂-alkyl)-aminocarbonyl-C₁₋₃-alkyl,            (C₁₋₂-alkyl-carbonyl)-amino-C₁₋₃-alkyl,            (C₁₋₄-alkoxy-carbonyl)-amino-C₁₋₃-alkyl,            (phenyl-carbonyl)-amino-C₁₋₃-alkyl,            (C₃₋₆-cycloalkyl-carbonyl)-amino-C₁₋₃-alkyl,            (C₃₋₆-cycloalkyl-C₁₋₃-alkyl-carbonyl)-amino-C₁₋₃-alkyl,            (thiophen-2-yl-carbonyl)-amino-C₁₋₃-alkyl,            (furan-2-yl-carbonyl)-amino-C₁₋₃-alkyl,            (phenyl-C₁₋₃-alkyl-carbonyl)-amino-C₁₋₃-alkyl,            (2-(C₁₋₄-alkoxy)-benzoyl-carbonyl)-amino-C₁₋₃-alkyl,            (pyridin-2-yl-carbonyl)-amino-C₁₋₃-alkyl,            (pyridin-3-yl-carbonyl)-amino-C₁₋₃-alkyl,            (pyridin-4-yl-carbonyl)-amino-C₁₋₃-alkyl or            C₁₋₃-alkyl-piperazin-1-yl-carbonyl-C₁₋₃-alkyl group,        -   by an aminocarbonyl-C₂₋₃-alkenyl,            (C₁₋₃-alkylamino)-carbonyl-C₂₋₃-alkenyl,            di-(C₁₋₃-alkyl)-amino-carbonyl-C₂₋₃-alkenyl or            C₁₋₄-alkoxy-carbonyl-C₂₋₃-alkenyl group;    -   II.iii. R² and R⁴ are as defined under I. and    -   R³ is a phenyl group substituted by a carboxy-C₁₋₃-alkyl or        C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl group;    -   II.iv. R³ and R⁴ are as defined under I. and    -   R² is a fluorine or chlorine atom;    -   II.v. R² and R³ are as defined under I. and    -   R⁴ is a phenyl group or a phenyl group which is monosubstituted        -   by a C₁₋₃-alkyl group which is terminally substituted by an            amino, guanidino, mono- or di-(C₁₋₂-alkyl)-amino-,            N—[ω-di-(C₁₋₃-alkyl)-amino-C₂₋₃-alkyl]-N—(C₁₋₃-alkyl)-amino,            N-methyl-(C₃₋₄-alkyl)-amino, N—(C₁₋₃-alkyl)-N-benzylamino,            N—(C₁₋₄-alkoxycarbonyl)-amino,            N—(C₁₋₄-alkoxycarbonyl)-C₁₋₄-alkylamino,            4-(C₁₋₃-alkyl)-piperazin-1-yl, imidazol-1-yl,            pyrrolidin-1-yl, azetidin-1-yl, morpholin-4-yl,            piperazin-1-yl, thiomorpholin-4-yl group,        -   by a di-(C₁₋₃-alkyl)-amino-(C₁₋₃-alkyl)-sulphonyl,            2-[di-(C₁₋₃-alkyl)-amino]-ethoxy,            4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl,            {ω-[di-(C₁₋₃-alkyl)-amino]-(C₂₋₃-alkyl)}-N—(C₁₋₃-alkyl)-amino-carbonyl,            1-(C₁₋₃-alkyl)imidazol-2-yl, (C₁₋₃-alkyl)-sulphonyl group,            or        -   by a group of the formula

-   -   -   in which            -   R⁷ is a C₁₋₂-alkyl, C₁₋₂-alkyl-carbonyl,                di-(C₁₋₂-alkyl)-amino-carbonyl-C₁₋₃-alkyl or                C₁₋₃-alkylsulphonyl group and            -   R⁸ is C₁₋₃-alkyl, ω-[di-(C₁₋₂-alkyl)-amino]-C₂₋₃-alkyl,                ω-[mono-(C₁₋₂-alkyl)-amino]-C₂₋₃-alkyl group, or        -   a (C₁₋₃-alkyl)-carbonyl, (C₄₋₆-alkyl)-carbonyl or            carbonyl-(C₁₋₃-alkyl) group which is terminally substituted            by a di-(C₁₋₂-alkyl)-amino, piperazin-1-yl or            4-(C₁₋₃-alkyl)-piperazin-1-yl group,        -   where all dialkylamino groups present in the radical R⁴ may            also be present in quaternized form, for example as an            N-methyl-(N,N-dialkyl)-ammonium group, where the counterion            is preferably selected from the group consisting of iodide,            chloride, bromide, methylsulphonate, para-toluenesulphonate            and trifluoroacetate.

-   III. Subgroups of particularly preferred compounds of the above    formula I which are to be mentioned in particular are those in    which:    -   III.i. X, R¹, R², R⁵ and R⁶ are as defined under I., R³ is as        defined under II.i. and R⁴ is as defined under II.v.;    -   III.ii. X, R¹, R², R⁵ and R⁶ are as defined under I., R³ is as        defined under II.ii. and R⁴ is as defined under II.v.;    -   III.iii. X, R¹, R², R⁵ and R⁶ are as defined under I., R³ is as        defined under II.iii. and R⁴ is as defined under II.v.;    -   III.iv. X, R¹, R⁵ and R⁶ are as defined under I., R² is as        defined under II.iv., R³ is as defined under II.i., II.ii. or        II.iii. and R⁴ is as defined under II.v.

A further preferred group of compounds of the above formula I are thosein which

X is an oxygen atom,R¹ is a hydrogen atom,R² is a fluorine, chlorine or bromine atom or a cyano group,R³ is a phenyl group or a phenyl group which is monosubstituted by afluorine, chlorine, bromine or iodine atom or by a C₁₋₃-alkoxy group,where the abovementioned unsubstituted and the monosubstituted phenylgroups may additionally be substituted in the 3- or 4-position

-   -   by a fluorine, chlorine or bromine atom,    -   by a C₁₋₃-alkoxy or C₁₋₂-alkyl-carbonyl-amino group,    -   by a carboxy-C₁₋₃-alkyl, aminocarbonyl-C₁₋₃-alkyl,        (C₁₋₂-alkylamino)-carbonyl-C₁₋₃-alkyl,        di-(C₁₋₂-alkyl)-aminocarbonyl-C₁₋₃-alkyl,        (C₁₋₂-alkyl-carbonyl)-amino-C₁₋₃-alkyl or        (phenyl-carbonyl)-amino-C₁₋₃-alkyl group,    -   where the substituents may be identical or different,        R⁴ is a phenyl group which is substituted    -   by a C₁₋₃-alkyl group terminally substituted by a        di-(C₁₋₂-alkyl)-amino group, or    -   by a group of the formula

-   -   in which        -   R⁷ is a C₁₋₂-alkyl, C₁₋₂-alkyl-carbonyl,            di-(C₁₋₂-alkyl)-amino-carbonyl-C₁₋₃-alkyl or            C₁₋₃-alkylsulphonyl group and        -   R⁸ is a C₁₋₃-alkyl or ω-[di-(C₁₋₂-alkyl)-amino]-C₂₋₃-alkyl            group, or        -   a C₁₋₃-alkyl-carbonyl group terminally substituted by a            di-(C₁₋₂-alkyl)-amino, piperazino or            4-(C₁₋₃-alkyl)-piperazin-1-yl group,            R⁵ is a hydrogen atom and            R⁶ is a hydrogen atom,            where the abovementioned alkyl groups include linear and            branched alkyl groups in which additionally one to 3            hydrogen atoms may be replaced by fluorine atoms,            where additionally a carboxyl, amino or imino group present            may be substituted by an in vivo cleavable radical,            their tautomers, enantiomers, diastereomers, their mixtures            and their salts.

The following compounds of the formula I are particularly preferred:

-   (a)    3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (b)    3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (c)    3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (d)    3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (e)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (f)    3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (g)    3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (h)    3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (i)    3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (j)    3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (k)    3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (l)    3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (m)    3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (n)    3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (o)    3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (p)    3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (q)    3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)-methylene]-6-bromo-2-indolinone    where additionally a carboxyl, amino or imino group present may be    substituted by an in vivo cleavable radical or may be present in the    form of a prodrug radical, for example in the form of a group which    can be converted in vivo into a carboxyl group or in the form of a    group which can be converted in vivo into an imino or amino group,    and their salts.

A group which can be converted in vivo into a carboxyl group is to beunderstood as meaning, for example, a hydroxymethyl group, a carboxylgroup which is esterified with an alcohol in which the alcoholic moietyis preferably a C₁₋₆-alkanol, a phenyl-C₁₋₃-alkanol, aC₃₋₉-cycloalkanol, where a C₅₋₈-cycloalkanol may additionally besubstituted by one or two C₁₋₃-alkyl groups, a C₅₋₈-cycloalkanol inwhich one methylene group in the 3- or 4-position is replaced by anoxygen atom or by an imino group optionally substituted by a C₁₋₃-alkyl,phenyl-C₁₋₃-alkyl, phenyl-C₁₋₃-alkoxy-carbonyl or C₁₋₆-alkyl-carbonylgroup and in which the cycloalkanol moiety may additionally besubstituted by one or two C₁₋₃-alkyl groups, a C₄₋₇-cycloalkenol, aC₃₋₅-alkenol, a phenyl-C₃₋₅-alkenol, a C₃₋₅-alkynol or aphenyl-C₃₋₅-alkynol, with the proviso that no bond to the oxygen atomoriginates from a carbon atom which carries a double or triple bond, aC₃₋₈-cycloalkyl-C₁₋₃-alkanol, a bicycloalkanol having a total of 8 to 10carbon atoms which may additionally be substituted in the bicycloalkylmoiety by one or two C₁₋₃-alkyl groups, a1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of the formula

R_(a)—CO—O—(R_(b)CR_(c))—OH,

-   -   in which    -   R_(a) is a C₁₋₈-alkyl, C₅₋₇-cycloalkyl, phenyl or        phenyl-C₁₋₃-alkyl group,    -   R_(b) is a hydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl or        phenyl group, and    -   R_(c) is a hydrogen atom or a C₁₋₃-alkyl group,        and a radical cleavable in vivo from an imino or amino group is        to be understood as meaning, for example, a hydroxyl group, an        acyl group, such as the benzoyl or pyridinoyl group, or a        C₁₋₁₆-alkylcarbonyl group, such as the formyl, acetyl,        propionyl, butanoyl, pentanoyl or hexanoyl group, an        allyloxycarbonyl group, a C₁₋₁₆-alkoxy-carbonyl group, such as        the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,        isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl,        pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl,        nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl,        dodecyloxycarbonyl or hexadecyloxycarbonyl group, a        phenyl-C₁₋₆-alkoxy-carbonyl group, such as the        benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl        group, a C₁₋₃-alkylsulphonyl-C₁₋₄-alkoxy-carbonyl,        C₁₋₃-alkoxy-C₂₋₄-alkoxy-C₂₋₄-alkoxy-carbonyl or        R_(a)CO—O—(R_(b)CR_(c))—O—CO— group, in which    -   R_(a) is a C₁₋₈-alkyl, C₅₋₇-cycloalkyl, phenyl or        phenyl-C₁₋₃-alkyl group,    -   R_(b) is a hydrogen atom, a C₁₋₃-alkyl, C₅₋₇-cycloalkyl or        phenyl group and    -   R_(c) is a hydrogen atom, a C₁₋₃-alkyl or        R_(a)CO—O—(R_(b)CR_(c))—O— group, in which R_(a) to R_(c) are as        defined above,        and additionally, for an amino group, the phthalimido group,        where the ester radicals mentioned above can also be used as a        group which can be converted in vivo into a carboxyl group.

Preferred prodrug radicals for a carboxyl group are aC₁₋₆-alkoxy-carbonyl group, such as the methoxycarbonyl, ethoxycarbonyl,n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl,n-pentyloxycarbonyl, n-hexyloxycarbonyl or cyclohexyloxycarbonyl group,or a phenyl-C₁₋₃-alkoxy-carbonyl group, such as the benzyloxycarbonylgroup, and,

for an imino or amino group, a C₁₋₉-alkoxy-carbonyl group, such as themethoxy-carbonyl, ethoxycarbonyl, n-propyloxycarbonyl,isopropyloxycarbonyl, n-butyloxy-carbonyl, n-pentyloxycarbonyl,n-hexyloxycarbonyl, cyclohexyloxycarbonyl, n-heptyloxycarbonyl,n-octyloxycarbonyl or n-nonyloxycarbonyl group, aphenyl-C₁₋₃-alkoxy-carbonyl group, such as the benzyloxycarbonyl group,a phenylcarbonyl group optionally substituted by a C₁₋₃-alkyl group,such as the benzoyl or 4-ethyl-benzoyl group, a pyridinoyl group, suchas the nicotinoyl group, a C₁₋₃-alkylsulphonyl-n-C₂₋₃-alkoxy-carbonyl orC₁₋₃-alkoxy-C₂₋₃-alkoxy-C₁₋₄-alkoxy-carbonyl group, such as the2-methylsulphonylethoxycarbonyl or 2-(2-ethoxy)-ethoxycarbonyl group.

According to the invention, the novel compounds are obtained, forexample, by the following processes, which are known in principle fromthe literature:

a. reaction of a compound of the formula

in whichthe radicals Z¹ and R³ may, if appropriate, change their positions,X, R², R³ and R⁶ are as defined at the outset,R¹′ has the meanings mentioned at the outset for R¹ or is a protectivegroup for the nitrogen atom of the lactam group, where R¹ may also, ifappropriate, represent a bond, formed via a spacer, to a solid phase,and Z¹ is a halogen atom, a hydroxyl, alkoxy or arylalkoxy group, forexample a chlorine or bromine atom, a methoxy, ethoxy or benzyloxygroup,with an amine of the formula

in whichR⁴ and R⁵ are defined as mentioned at the outset,and, if required, the product is subsequently cleaved from a protectivegroup used for the nitrogen atom of the lactam group or from a solidphase.

Suitable protective groups for the nitrogen atom of the lactam groupare, for example, an acetyl, benzoyl, ethoxycarbonyl,tert-butyloxycarbonyl or benzyloxycarbonyl group and

suitable solid phases are a resin, such as a4-(2′,4′-dimethoxyphenylaminomethyl)-phenoxy resin, where the attachmentis expediently via the amino group, or a p-benzyloxybenzyl alcoholresin, where the attachment is expediently via a spacer, such as a2,5-dimethoxy-4-hydroxybenzyl derivative.

The reaction is expediently carried out in a solvent, such asdimethylformamide, toluene, acetonitrile, tetrahydrofuran, dimethylsulphoxide, methylene chloride or a mixture thereof, if appropriate inthe presence of an inert base, such as triethylamine,N-ethyldiisopropylamine or sodium bicarbonate, at temperatures between20 and 175° C., where any protective groups used may be simultaneouslyremoved owing to transamidation.

If, in a compound of the formula V, Z¹ is a halogen atom, the reactionis preferably carried out in the presence of an inert base attemperatures between 20 and 120° C.

If, in a compound of the formula V, Z¹ is a hydroxyl, alkoxy orarylalkoxy group, the reaction is preferably carried out at temperaturesbetween 20 and 200° C.

The subsequent removal of a protective group used, which may berequired, if appropriate, is expediently carried out eitherhydrolytically in an aqueous or alcoholic solvent, for example inmethanol/water, ethanol/water, isopropanol/water, tetrahydrofuran/water,dioxane/water, dimethylformamide/water, methanol or ethanol, in thepresence of an alkali metal base, such as lithium hydroxide, sodiumhydroxide or potassium hydroxide, at temperatures between 0 and 100° C.,preferably at temperatures between 10 and 50° C.,

or, advantageously, by transamidation with an organic base, such asammonia, butylamine, dimethylamine or piperidine, in a solvent, such asmethanol, ethanol, dimethylformamide and mixtures thereof, or in anexcess of the amine used, at temperatures between 0 and 100° C.,preferably at temperatures between 10 and 50° C.

Cleavage from a solid phase employed is preferably carried out usingtrifluoroacetic acid and water at temperatures between 0 and 35° C.,preferably at room temperature.

b. To prepare a compound of the formula I in which R³ is a phenyl ornaphthyl group substituted by a carboxy-C₂₋₃-alkenyl,aminocarbonyl-C₂₋₃-alkenyl, (C₁₋₃-alkylamino)-carbonyl-C₂₋₃-alkenyl,di-(C₁₋₃-alkylamino)-carbonyl-C₂₋₃-alkenyl orC₁₋₄-alkoxy-carbonyl-C₂₋₃-alkenyl group,reaction of a compound of the formula

in whichR², R⁴, R⁵, R⁶ and X are as defined at the outset,R¹′ has the meanings mentioned at the outset for R¹ or is a protectivegroup for the nitrogen atom of the lactam group, where R¹′ may also, ifappropriate, represent a bond, formed via a spacer, to a solid phase,andZ³ is a leaving group, for example a halogen atom or an alkyl- orarylsulphonyloxy group, such as a chlorine, bromine or iodine atom or amethylsulphonyloxy, ethylsulphonyloxy, p-toluenesulphonyloxy ortrifluoromethanesulphonyloxy group, with an alkene of the formula

in which

R³′ is an amino, (C₁₋₃-alkylamino), di-(C₁₋₃-alkylamino) or C₁₋₄-alkoxygroup and

n is the number 0 or 1.

The reaction is expediently carried out with palladium catalysis, using,for example, palladium(II) acetate, palladium(II) chloride,bis(triphenylphosphine)palladium(II) acetate,bis(triphenylphosphine)palladium(II) chloride, palladium/carbon,bis-[1,2-bis(diphenylphosphino)ethane]palladium(0),dichloro-(1,2-bis(diphenylphosphino)-ethane)palladium(II),tetrakistriphenylphosphinepalladium(0),tris(dibenzylidene-acetone)dipalladium(0),1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) ortris(dibenzylideneacetone)dipalladium(0)/chloroform adduct, in thepresence of a base, such as triethylamine, diisopropylethylamine,lithium carbonate, potassium carbonate, sodium carbonate, caesiumcarbonate, and a ligand, such as triphenylphosphine,tri-ortho-tolylphosphine or tri-(tert-butyl)phosphine, in solvents suchas acetonitrile, N-methylpyrrolidinone, dioxane or dimethylformamide andmixtures thereof.

The cleavage of a protective group used for the nitrogen atoms of thelactam group or from a solid phase, which may be required, ifappropriate, is carried out as described above under process (a).

c. To prepare a compound of the formula I in which R³ is a phenyl ornaphthyl group substituted by

-   -   a carboxy-C₁₋₃-alkyl, C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl,        aminocarbonyl-C₁₋₃-alkyl, (C₁₋₃-alkylamino)-carbonyl-C₁₋₃-alkyl        or di-(C₁₋₃-alkyl)-aminocarbonyl-C₁₋₃-alkyl group,        hydrogenation of a compound of the formula

in whichR², R⁴, R⁵, R⁶ and X are as defined at the outset,R¹′ has the meanings mentioned at the outset for R¹ or is a protectivegroup for the nitrogen atom of the lactam group, where R¹′ may also, ifappropriate, represent a bond, formed via a spacer, to a solid phase,A is a C₂₋₃-alkenyl group andR^(3′) is a hydroxyl, C₁₋₄-alkoxy, amino, (C₁₋₃-alkylamino) ordi-(C₁₋₃-alkyl)amino group.

The hydrogenation is preferably carried out using catalytichydrogenation with hydrogen in the presence of a catalyst, such aspalladium/carbon or platinum, in a solvent, such as methanol, ethanol,ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacialacetic acid, if appropriate with addition of an acid, such ashydrochloric acid, at temperatures between 0 and 50° C., but preferablyat room temperature, and at a hydrogen pressure of 1 to 7 bar, butpreferably 3 to 5 bar.

The cleavage of a protective group used for the nitrogen atom of thelactam group or from a solid phase, which may be required, ifappropriate, is carried out as described under process (a).

If, according to the invention, a compound of the formula I is obtainedwhich contains an alkoxycarbonyl group, this can be converted byhydrolysis into a corresponding carboxyl compound, or

if a compound of the formula I is obtained which contains an amino oralkylamino group, this can be converted by reduction alkylation into acorresponding alkylamino or dialkylamino compound, orif a compound of the formula I is obtained which contains a dialkylaminogroup, this can be converted by alkylation into a correspondingtrialkylammonium compound, orif a compound of the formula I is obtained which contains an amino oralkylamino group, this can be converted by acylation or sulphonationinto a corresponding acyl or sulphonyl compound, respectively, orif a compound of the formula I is obtained which contains a carboxylgroup, this can be converted by esterification or amidation into acorresponding ester or aminocarbonyl compound, respectively, orif a compound of the formula I is obtained which contains a nitro group,this can be converted by reduction into a corresponding amino compound,orif a compound of the formula I is obtained which contains a cyano group,this can be converted by reduction into a corresponding aminomethylcompound, orif a compound of the formula I is obtained which contains anarylalkyloxy group, this can be converted with acid into a correspondinghydroxyl compound, orif a compound of the formula I is obtained which contains analkoxycarbonyl group, this can be converted by hydrolysis into acorresponding carboxyl compound, orif a compound of the formula I is obtained in which R₄ is a phenyl groupsubstituted by an amino, alkylamino, aminoalkyl or N-alkylamino group,this can then be converted by reaction with a corresponding cyanate,isocyanate or carbamoyl halide into a corresponding urea compound of theformula I, orif a compound of the formula I is obtained in which R₄ is a phenyl groupsubstituted by an amino, alkylamino, aminoalkyl or N-alkylamino group,this can subsequently be converted by reaction with a correspondingamidino-group-transferring compound or by reaction with a correspondingnitrile into a corresponding guanidino compound of the formula I.

The subsequent hydrolysis is preferably carried out in an aqueoussolvent, for example in water, methanol/water, ethanol/water,isopropanol/water, tetrahydrofuran/water or dioxane/water, in thepresence of an acid, such as trifluoroacetic acid, hydrochloric acid orsulphuric acid, or in the presence of an alkali metal base, such aslithium hydroxide, sodium hydroxide or potassium hydroxide, attemperatures between 0 and 100° C., preferably at temperatures between10 and 50° C.

The subsequent reductive alkylation is preferably carried out in asuitable solvent, such as methanol, methanol/water,methanol/water/ammonia, ethanol, ether, tetrahydrofuran, dioxane ordimethylformamide, if appropriate with addition of an acid, such ashydrochloric acid, in the presence of catalytically activated hydrogen,for example of hydrogen in the presence of Raney nickel, platinum orpalladium/carbon, or in the presence of a metal hydride, such as sodiumborohydride, lithium borohydride, sodium cyanoborohydride or lithiumaluminium hydride, at temperatures between 0 and 100° C., preferably attemperatures between 20 and 80° C.

The subsequent alkylation is preferably carried out in a suitablesolvent, such as ether, tetrahydrofuran, dioxane, dichloromethane,acetone or acetonitrile, in the presence of alkylating agents, such asalkyl iodides, alkyl bromides, alkyl chlorides, methanesulphonic acidalkyl esters, para-toluenesulphonic acid alkyl esters or alkyltrifluoroacetates, at temperatures between 0 and 100° C., preferably attemperatures between 20 and 60° C.

The subsequent acylation or sulphonylation is expediently carried outusing the corresponding free acid or a corresponding reactive compound,such as its anhydride, ester, imidazolide or halide, preferably in asolvent, such as methylene chloride, diethyl ether, tetrahydrofuran,toluene, dioxane, acetonitrile, dimethyl sulphoxide ordimethylformamide, if appropriate in the presence of an inorganic or atertiary organic base, at temperatures between −20 and 200° C.,preferably at temperatures between 20° C. and the boiling point of thesolvent used. The reaction with the free acid can, if appropriate, becarried out in the presence of an agent which activates the acid or of adehydrating agent, for example in the presence of isobutylchloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate,2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride,trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide,N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide,N,N′-dicyclohexyl-carbodiimide/1-hydroxybenzotriazole,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl uroniumtetrafluoroborate/1-hydroxybenzotriazole, N,N′-carbonyldiimidazole ortriphenylphosphine/carbon tetrachloride, and, if appropriate, withaddition of a base, such as pyridine, 4-dimethylaminopyridine,N-methylmorpholine or triethylamine, expediently at temperatures between0 and 150° C., preferably at temperatures between 0 and 100° C. Thereaction with a corresponding reactive compound can, if appropriate, becarried out in the presence of a tertiary organic base, such astriethylamine, N-ethyl-diisopropylamine, N-methylmorpholine or pyridine,or, if an anhydride is used, in the presence of the corresponding acids,at temperatures between 0 and 150° C., preferably at temperaturesbetween 50 and 100° C.

The subsequent esterification or amidation is expediently carried out byreacting a reactive corresponding carboxylic acid derivative with anappropriate alcohol or amine, as described above.

The esterification or amidation is preferably carried out in a solvent,such as methylene chloride, diethyl ether, tetrahydrofuran, toluene,dioxane, acetonitrile, dimethyl sulphoxide or dimethylformamide, ifappropriate in the presence of an inorganic or a tertiary organic base,preferably at temperatures between 20° C. and the boiling point of thesolvent used. Here, the reaction with a corresponding acid is preferablycarried out in the presence of a dehydrating agent, for example in thepresence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethylorthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionylchloride, trimethylchlorosilane, phosphorus trichloride, phosphoruspentoxide, N,N′-dicyclohexylcarbodiimide,N,N′-dicyclohexylcarbodiimide/N-hydroxysuccinimide,N,N′-dicyclohexylcarbodiimide/1-hydroxybenzotriazole,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate,2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumtetrafluoroborate/1-hydroxybenzotriazole, N,N′-carbonyldiimidazole ortriphenyl-phosphine/carbon tetrachloride, and, if appropriate, withaddition of a base, such as pyridine, 4-dimethylaminopyridine,N-methylmorpholine or triethylamine, expediently at temperatures between0 and 150° C., preferably at temperatures between 0 and 100° C., and theacylation with a corresponding reactive compound, such as its anhydride,ester, imidazolide or halide, is, if appropriate, carried out in thepresence of a tertiary organic base, such triethylamine,N-ethyldiisopropylamine or N-methylmorpholine, at temperatures between 0and 150° C., preferably at temperatures between 50 and 100° C.

The subsequent reduction of a nitro group is preferably carried outhydrogenolytically, for example with hydrogen in the presence of acatalyst, such as palladium/carbon or Raney nickel, in a solvent, suchas methanol, ethanol, ethyl acetate, dimethylformamide,dimethylformamide/acetone or glacial acetic acid, if appropriate withaddition of an acid, such as hydrochloric acid or glacial acetic acid,at temperatures between 0 and 50° C., but preferably at roomtemperature, and at a hydrogen pressure of from 1 to 7 bar, butpreferably from 3 to 5 bar.

The subsequent hydrogenation of a cyano group is preferably carried outhydrogenolytically, for example using hydrogen in the presence of acatalyst, such as palladium/carbon or Raney nickel, in a solvent, suchas methanol, ethanol, ethyl acetate, methylene chloride,dimethylformamide, dimethylformamide/acetone or glacial acetic acid, ifappropriate with addition of an acid, such as hydrochloric acid orglacial acetic acid, at temperatures between 0 and 50° C., butpreferably at room temperature, and at a hydrogen pressure of from 1 to7 bar, but preferably of from 3 to 5 bar.

The subsequent preparation of a corresponding guanidino compound of theformula I is expediently carried out by reaction with anamidino-group-transferring compound, such as3,5-dimethylpyrazole-1-carboxamidine, preferably in a solvent, such asdimethylformamide, and, if appropriate, in the presence of a tertiaryorganic base, such as triethylamine, at temperatures between 0 and 50°C., preferably at room temperature.

In the reactions described above, any reactive groups present, such ascarboxyl, hydroxyl, amino, alkylamino or imino groups, can be protectedduring the reaction by customary protective groups which are removedagain after the reaction.

A protective radical for a carboxyl group is, for example, thetrimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranylgroup, and

a protective group for a hydroxyl, amino, alkylamino or imino group is,for example, the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl,tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or2,4-dimethoxybenzyl group, and, for the amino group, additionally thephthalyl group.

The subsequent removal of a protective radical used is, if appropriate,carried out, for example, hydrolytically in an aqueous solvent, forexample in water, isopropanol/water, tetrahydrofuran/water ordioxane/water, in the presence of an acid, such as trifluoroacetic acid,hydrochloric acid or sulphuric acid, or in the presence of an alkalimetal base, such as lithium hydroxide, sodium hydroxide or potassiumhydroxide, at temperatures between 0 and 100° C., preferably attemperatures between 10 and 50° C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl radical isremoved, for example, hydrogenolytically, for example using hydrogen inthe presence of a catalyst, such as palladium/carbon, in a solvent suchas methanol, ethanol, ethyl acetate, dimethylformamide,dimethylformamide/acetone or glacial acetic acid, if appropriate withaddition of an acid, such as hydrochloric acid or glacial acetic acid,at temperatures between 0 and 50° C., but preferably at roomtemperature, and at a hydrogen pressure of from 1 to 7 bar, butpreferably of from 3 to 5 bar.

A methoxybenzyl group can also be removed in the presence of anoxidizing agent, such as cerium(IV) ammonium nitrate, in a solvent, suchas methylene chloride, acetonitrile or acetonitrile/water, attemperatures between 0 and 50° C., but preferably at room temperature.

However, a 2,4-dimethoxybenzyl radical is preferably removed intrifluoroacetic acid in the presence of anisole.

A tert-butyl or tert-butyloxycarbonyl radical is preferably removed bytreatment with an acid, such as trifluoroacetic acid or hydrochloricacid, using, if appropriate, a solvent, such as methylene chloride,dioxane, ethyl acetate or ether.

A phthalyl radical is preferably removed in the presence of hydrazine ora primary amine, such as methylamine, ethylamine or n-butylamine, in asolvent, such as methanol, ethanol, isopropanol, toluene/water ordioxane, at temperatures between 20 and 50° C.

Furthermore, chiral compounds of the formula I obtained can be separatedinto their enantiomers and/or diastereomers.

Thus, for example, compounds of the formula I obtained which occur asracemates can be separated by methods known per se (see Allinger N. L.and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6, WileyInterscience, 1971) into their enantiomers, and compounds of the formulaI having at least 2 asymmetric carbon atoms can, owing to theirphysicochemical differences, be separated by methods known per se, forexample by chromatography and/or fractional crystallization, into theirdiastereomers, which, if they are obtained in racemic form, can then beseparated into the enantiomers as mentioned above.

The separation of enantiomers is preferably carried out by columnseparation on chiral phases or by recrystallization from an opticallyactive solvent or by reaction with an optically active substance whichforms salts or derivatives, such as, for example, esters or amides, withthe racemic compound, in particular acids and their activatedderivatives or alcohols, and separating the mixture of diastereomericsalts or derivatives obtained in this manner, for example owing todifferent solubilities, whereupon the free enantiomers can be releasedfrom the pure diastereomeric salts or derivatives by action of suitableagents. Particularly common optically active acids are, for example, theD and L forms of tartaric acid, dibenzoyltartaric acid,di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonicacid, glutamic acid, N-acetylglutamic acid, aspartic acid,N-acetylaspartic acid or quinic acid. A suitable optically activealcohol is, for example, (+)- or (−)-menthol, and a suitable opticallyactive acyl radical in amides is, for example, the (+)- or(−)-methyloxycarbonyl radical.

Furthermore, the compounds of the formula I obtained can be convertedinto their salts, in particular, for pharmaceutical use, into theirphysiologically acceptable salts, with inorganic or organic acids. Acidssuitable for this purpose are, for example, hydrochloric acid,hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid,succinic acid, lactic acid, citric acid, tartaric acid, maleic acid,methanesulphonic acid, ethanesulphonic acid, para-toluenesulphonic acid,phenylsulphonic acid or L-(+)-mandelic acid.

Moreover, the resulting novel compounds of the formula I can, if theycontain a carboxyl group, then, if desired, be converted into theirsalts with inorganic or organic bases, in particular, for pharmaceuticaluse, into their physiologically acceptable salts. Bases suitable forthis purpose are, for example, sodium hydroxide, potassium hydroxide,cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

Also suitable, for compounds of the formula I which contain 2 or moreacidic or basic groups, are salts with 2 or more inorganic or organicbases or acids (disalts etc.).

Some of the compounds of the general formulae V to XI used as startingmaterials are known from the literature or can be obtained by processesknown from the literature or can be obtained by the processes describedabove and in the examples. Compounds of the general formula IX, forexample, are described in the German patent application 198 44 003.

As already mentioned at the outset, the novel compounds of the formula(I) have useful pharmacological properties, in particular in inhibitingaction on various kinases, especially on receptor tyrosine kinases, suchas VEGFR1, VEGFR2, VEGFR3, PDGFRα, PDGFRβ, FGFR1, FGFR3, EGFR, HER2,c-Kit, IGF1R and HGFR, Flt-3, and on the proliferation of cultivatedhuman cells, in particular that of endothelial cells, for example inangiogenesis, but also on the proliferation of other cells, inparticular of tumour cells.

The biological properties of the novel compounds were examined by thefollowing standard methods:

Human umbilical cord endothelial cells (HUVEC) were cultivated in IMDM(Gibco BRL), supplemented with 10% foetal bovine serum (FBS) (Sigma), 50μM β-mercaptoethanol (Fluka), standard antibiotics, 15 μg/ml ofendothelial cell growth factor (ECGS, Collaborative Biomedical Products)and 100 μg/ml of heparin (Sigma) on gelatin-coated culture bottles (0.2%gelatin, Sigma) at 37° C., 5% CO₂, in an atmosphere saturated withwater.

To examine the inhibitory activity of the compounds according to theinvention, the cells were “starved” for 16 hours, i.e. kept in culturemedium without growth factors (ECGS+heparin). Using trypsin/EDTA, thecells were detached from the culture bottles and washed once withserum-containing medium. 2.5×10³ cells were then seeded in each well.

The proliferation of the cells was stimulated using 5 ng/ml of VEGF₁₆₅(vascular endothelial growth factor; H. Weich, GBF Brunswick) and 10μg/ml of heparin. Per plate, as control value, in each case 6 wells werenot stimulated.

The compounds according to the invention were dissolved in 100% dimethylsulphoxide and, in triplicate, added to the cultures in differentdilutions, the maximum dimethyl sulphoxide concentration being 0.3%.

The cells were incubated at 37° C. for 76 hours, and ³H-thymidine (0.1μCi/well, Amersham) was then added for a further 16 hours to determineDNA synthesis. The radioactively labelled cells were then immobilized onfilter mats and the incorporated radioactivity was determined in a βcounter. To determine the inhibitory activity of the compounds accordingto the invention, the mean value for the non-stimulated cells wassubtracted from the mean value of the factor-stimulated cells (in thepresence or absence of the compounds according to the invention).

The relative cell proliferation was calculated in percent of the control(HUVEC without inhibitor), and the concentration of active compound atwhich the proliferation of the cells is inhibited by 50% (IC₅₀) wasderived therefrom.

The compounds of the formula I according to the invention have an IC₅₀between 50 μM and 1 nM.

Owing to their inhibitory action on the proliferation of cells, inparticular of endothelian cells and of tumour cells, the compounds ofthe formula I are suitable for treating diseases in which theproliferation of cells, in particular that of endothelial cells, plays arole.

Thus, for example, the proliferation of endothelial cells and therelated neovascularization is a decisive step in tumour progression(Folkman J. et al., Nature 339, 58-61, (1989); Hanahan D. and FolkmanJ., Cell 86, 353-365, (1996)). Furthermore, the proliferation ofendothelial cells is also of importance in haemangiomes, inmetastasization, in rheumatoid arthritis, in psoriasis and in ocularneovascularization (Folkman J., Nature Med. 1, 27-31, (1995); CarmelietP & Rakeh J., Nature 407, 249-257, (2000)). The therapeutic benefit ofinhibitors of endothelial cell proliferation in the animal model wasshown, for example, by O'Reilly et al. and Parangi et al. (O'Reilly M.S. et al., Cell 88, 277-285, (1997); Parangi S. et al., Proc Natl AcadSci USA 93, 2002-2007, (1996)).

Thus, the compounds of the formula I, their tautomers, theirstereoisomers or their physiologically acceptable salts are suitable,for example, for treating tumours (for example squamous epitheliumcarcinoma, astrocytoma, Kaposi sarcoma, glioblastoma, lung cancer,cancer of the bladder, neck carcinoma, oesophagus carcinoma, melanoma,ovarial carcinoma, prostate carcinoma, breast cancer, small-cell lungcarcinoma, glioma, colorectal carcinoma, pancreas carcinoma, urogenitalcancer and gastrointestinal carcinoma, and also haematological cancers,such as, for example, multiple myeloma and acute myelotic leukaemia),psoriasis, arthritis (for example rheumatoid arthritis), haemangioma,angiofibroma, disorders of the eye (for example diabetic retinopathy),neovascular glaucoma, disorders of the kidneys (for exampleglomerulonephritis), diabetic nephropathy, malignant nephrosclerosis,thrombic microangiopathic syndromes, transplantation rejections andglomerulopathy, fibrotic disorders (for example cirrhosis of the liver),mesangial-cell-proliferative disorders, atherosclerosis, injuries of thenerve tissue and for inhibiting the reocclusion of vessels after ballooncatheter treatment, in vessel prosthetics or after implantation ofmechanical devices for keeping vessels open (for example stents) orother disorders in which cell proliferation or angiogenesis play a role.

Owing to their biological properties, the compounds according to theinvention can be used alone or in combination with otherpharmacologically active compounds, for example in tumour therapy inmonotherapy or in combination with other antitumor therapeutics, forexample in combination with topoisomerase inhibitors (for exampleetoposide), mitosis inhibitors (for example vinblastine, Taxol),compounds which interact with nucleic acids (for example cisplatin,cyclophosphamide, adriamycin), hormone antagonists (for exampletamoxifen), steroids and analogues thereof (for example dexamethasone),inhibitors of metabolic processes (for example 5-FU etc.), cytokines(for example interferons), kinase inhibitors (for example EGFR kinaseinhibitoren, such as, for example, Iressa; Gleevec), allostericallyacting receptor tyrosine kinase inhibitors, antibodies (for exampleHerceptin), COX-2 inhibitors or else in combination with radiotherapy,etc. These combinations can be administered either simultaneously orsequentially.

The invention is illustrated in more detail by the examples below:

Example Name 1.03-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-iodophenyl)-methylene]-6-chloro-2-indolinone 1.13-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-iodophenyl)methylene]-6-chloro-2-indolinone 1.23-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone 1.33-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone 1.43-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone1.5 3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone 1.63-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone 1.73-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone 1.83-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone 1.93-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone 1.103-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3,4-dimethoxyphenyl)-methylene]-6-chloro-2-indolinone 1.113-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylcarbamoyl)anilino)-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone 2.03-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-cyanophenyl)-methylene]-6-chloro-2-indolinone 3.03-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-iodophenyl)methylene]-6-fluoro-2-indolinone 3.13-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone 3.23-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone 3.33-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-fluorophenyl)methylene]-6-fluoro-2- indolinone3.4 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.53-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.63-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.7 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.83-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-iodophenyl)methylene]-6-fluoro-2-indolinone 3.9 3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.103-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.113-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.123-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.133-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-cyanomethylphenyl)-methylene]-6-fluoro-2-indolinone 3.143-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.153-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.163-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.173-Z-[1-(4-(N-Acetyl-N-methylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.183-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.193-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.203-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.213-Z-[1-(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.223-Z-[1-(4-(4-methylpiperazin-1-yl-carbonyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.233-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.243-Z-[1-(4-methylsulphonylanilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.253-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.263-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.273-Z-[1-(4-(4-methylpiperazin-1-yl-carbonyl)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.283-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.293-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.303-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.313-Z-[1-(4-(N-(4-dimethylamino-butylcarbonyl)-N-methylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.323-Z-[1-Anilino-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.33 3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.343-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.353-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)-methylene]-6-fluoro-2-indolinone 3.363-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.373-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.383-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.393-Z-[1-(4-methylsulphonylanilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.403-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.413-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.423-Z-[1-Anilino-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.433-Z-[1-(4-methylsulphonylanilino)-1-(3-methoxycarbonylmethylphenyl)-methylene]-6-fluoro-2-indolinone 3.443-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.453-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)-methylene]-6-fluoro-2-indolinone 3.463-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.473-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.483-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.493-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone3.503-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.513-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.523-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.533-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(3-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 3.543-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 3.553-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 3.563-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 3.573-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.583-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.593-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.603-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.613-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.623-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.633-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.643-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.653-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.663-Z-[1anilino-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.67 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.683-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.693-Z-[1-(4-(N-tert-butoxycarbonylaminomethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.703-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.713-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone 3.723-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.733-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 3.743-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 3.753-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 3.763-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.773-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.783-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.793-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.803-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.813-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.823-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.833-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 3.843-Z-[1anilino-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.853-Z-[1-(4-(N-tert-butoxycarbonylaminomethyl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.863-Z-[1-(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.873-Z-[1-(4-dimethylaminomethylanilino)-1-(3-methoxycarbonylmethoxy-phenyl)methylene]-6-fluoro-2-indolinone 3.883-Z-[1-(4-dimethylaminomethylanilino)-1-(4-methoxycarbonylmethoxy-phenyl)methylene]-6-fluoro-2-indolinone 3.893-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-ethoxycarbonyl-ethoxy)phenyl)methylene]-6-fluoro-2-indolinone 3.903-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone 3.913-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone 3.923-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone 3.933-Z-[1-(3-dimethylaminomethylanilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.943-Z-[1-(3-dimethylaminomethylanilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 3.953-Z-[1-(3-dimethylaminomethylanilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 4.03-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3,4-dimethoxyphenyl)-methylene]-6-cyano-2-indolinone 5.03-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-(2-methoxycarbonylvinyl)phenyl)methylene]-6-chloro-2-indolinone 5.13-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-methoxycarbonyl-vinyl)phenyl)methylene]-6-chloro-2-indolinone 5.23-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-carbamoyl-vinyl)phenyl)methylene]-6-fluoro-2-indolinone 5.33-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-methoxycarbonyl-vinyl)phenyl)methylene]-6-fluoro-2-indolinone 5.43-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(2-methoxycarbonyl-vinyl)phenyl)methylene]-6-fluoro-2-indolinone 6.03-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 6.13-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone 6.23-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 6.33-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 6.43-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 7.03-Z-[1-(4-dimethylaminomethylanilino)-1-(4-aminomethylphenyl)-methylene]-6-chloro-2-indolinone 8.03-Z-[1-(4-(N-((4-methylpiperazin-1-yl)methylcarbonyl)-N-methylamino)anilino)-1-(4-aminomethylphenyl)methylene]-6-chloro-2-indolinone 9.03-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-aminomethylphenyl)-methylene]-6-fluoro-2-indolinone 9.13-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.23-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-aminomethylphenyl)-methylene]-6-fluoro-2-indolinone 9.33-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-aminomethylphenyl)methylene]-6-fluoro-2-indolinone 9.4 3-Z-[1-(4-(methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.53-Z-[1-(4-(methylaminomethyl)anilino)-1-(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.63-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-aminomethylphenyl)methylene]-6-fluoro-2-indolinone 9.7 3-Z-[1-(4-(aminomethyl)anilino)-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.83-Z-[1-(4-(aminomethyl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 9.93-Z-[1-(4-(methylaminomethyl)anilino)-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.03-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 10.13-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.23-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.33-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.43-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.53-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.63-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.73-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.83-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.93-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.103-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.113-Z-[1-(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.123-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.133-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.143-Z-[1-(4-methylsulphonylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.153-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.163-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.173-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.183-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.193-Z-[1-Anilino-1-(3-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.203-Z-[1-(4-methylsulphonylanilino)-1-(3-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.213-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(3-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.223-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(3-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.233-Z-[1anilino-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2- indolinone10.243-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.253-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.263-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.273-Z-[1-(4-(4-methylpiperazin-1-yl-carbonyl)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.283-Z-[1-(4-methylsulphonylanilino)-1-(4-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.293-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.303-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.313-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.323-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.333-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.343-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-carboxymethylphenyl)methylene]-6-fluoro-2-indolinone 10.353-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.363-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.373-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.383-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.393-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.403-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.413-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.423-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.433-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.443-Z-[1-(4-(N-(4-dimethylamino-butylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.453-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.463-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.473-Z-[1anilino-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.48 3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.493-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.503-Z-[1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.513-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.523-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-carboxymethylphenyl)-methylene]-6-fluoro-2-indolinone 10.533-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 10.543-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 10.553-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 10.563-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.573-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.583-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.593-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.603-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.613-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 10.623-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.633-Z-[1anilino-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.643-Z-[1-(4-aminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.65 3-Z-[1-(4-methylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.663-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethoxy-phenyl)-methylene]-6-fluoro-2-indolinone 10.673-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethoxy-phenyl)phenyl)methylene]-6-fluoro-2-indolinone 10.683-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 10.693-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone 10.703-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)-methylene]-6-bromo-2-indolinone 10.713-Z-[1-(3-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.723-Z-[1-(3-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 10.733-Z-[1-(3-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone 11.03-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carbamoyl-ethyl)phenyl)methylene]-6-chloro-2-indolinone 11.13-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-chloro-2-indolinone 11.23-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.33-Z-[1-(4-dimethylaminomethylanilino)-1-(3-dimethylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.43-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.53-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.63-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-dimethylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.73-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carbamoylmethylphenyl)-methylene]-6-fluoro-2-indolinone 11.83-Z-[1-(4-dimethylaminomethylanilino)-1-(3-methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.93-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carbamoylmethylphenyl)-methylene]-6-fluoro-2-indolinone 11.103-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-dimethylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.113-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-(4-methylpiperazin-1-yl-carbonyl)ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.123-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-carbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.133-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-carbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.143-Z-[1-(4-dimethylaminomethylanilino)-1-(4-dimethylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.153-Z-[1-(4-dimethylaminomethylanilino)-1-(4-methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.163-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.173-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-dimethylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone11.18 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.193-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.203-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.213-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-methylcarbamoylethyl)phenyl)methylene]-6-fluoro-2-indolinone11.223-Z-[1-(4-(N-tert-butoxycarbonylmethylaminomethyl)anilino)-1-(4-(2-methylcarbamoylethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.233-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.243-Z-[1-(4-methylsulphonylanilino)-1-(4-(2-methylcarbamoyl-ethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.253-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-(2-methylcarbamoylethyl)phenyl)methylene]-6-fluoro-2-indolinone 11.263-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(3-methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 11.273-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-methylcarbamoylmethylphenyl)methylene]-6-fluoro-2-indolinone 12.03-Z-[1-(4-dimethylaminomethylanilino)-1-(4-acetylaminomethylphenyl)-methylene]-6-chloro-2-indolinone 12.13-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone 12.23-Z-[1-(4-dimethylaminomethylanilino)-1-(4-benzoylaminophenyl)-methylene]-6-chloro-2-indolinone 12.33-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-benzoylaminomethylphenyl)methylene]-6-chloro-2-indolinone 12.43-Z-[1-(4-dimethylaminomethylanilino)-1-(3-acetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.53-Z-[1-(4-dimethylaminomethylanilino)-1-(3-propionylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.63-Z-[1-(4-dimethylaminomethylanilino)-1-(3-benzoylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.73-Z-[1-(4-dimethylaminomethylanilino)-1-(3-phenylacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.83-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.93-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-benzoylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.103-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-propionylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.113-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-phenylacetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.123-Z-[1-(4-dimethylaminomethylanilino)-1-(4-acetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.133-Z-[1-(4-dimethylaminomethylanilino)-1-(4-propionylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.143-Z-[1-(4-dimethylaminomethylanilino)-1-(4-phenylacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.153-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-acetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.163-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-propionylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.173-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-phenylacetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.183-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-cyclopropylcarbonylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.193-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-cyclobutylcarbonylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.203-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-(pyridin-2-yl-carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.213-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-cyclohexylcarbonylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.223-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-(pyridin-3-yl-carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.233-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-isobutyrylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.243-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-(3-methylbutyrylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.253-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-cyclohexylmethylcarbonylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.26 3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-methoxyacetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.273-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-methoxybenzoyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.283-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-tert-butylacetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.293-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-thiophen-carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.303-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-pivaloylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.313-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-furoylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.323-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-acetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.333-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-propionylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.343-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-benzoylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.353-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-phenylacetylaminomethylphenyl)-methylene]-6-fluoro-2-indolinone 12.363-Z-[1-(4-dimethylaminomethylanilino)-1-(3-cyclopropylcarbonylaminomethylphenyl)methylene]-6-fluoro-2- indolinone12.37 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-cyclobutylcarbonylaminomethylphenyl)methylene]-6-fluoro-2-indolinone12.38 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(pyridin-2-yl-carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.393-Z-[1-(4-dimethylaminomethylanilino)-1-(3-cyclohexylcarbonylaminomethylphenyl)methylene]-6-fluoro-2- indolinone12.40 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(pyridin-3-yl-carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.413-Z-[1-(4-dimethylaminomethylanilino)-1-(3-isobutyrylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.423-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(3-methylbutyryl-aminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.433-Z-[1-(4-dimethylaminomethylanilino)-1-(3-cyclohexylmethylcarbonylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.44 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-methoxyacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.453-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-methoxybenzoyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.463-Z-[1-(4-dimethylaminomethylanilino)-1-(3-tert-butylacetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.473-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-thiophenecarbonylaminomethyl)phenyl)methylene]-6-fluoro-2- indolinone12.48 3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-pivaloylaminomethylphenyl)methylene]-6-fluoro-2-indolinone 12.493-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-furoylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 12.503-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(pyridin-4-yl-carbonylaminomethyl)phenyl)methylene]-6-fluoro-2-indolinone 13.03-Z-[1-(4-trimethylammoniummethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone iodide 13.13-Z-[1-(4-trimethylammoniummethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone iodide 14.03-Z-[1-(4-guanidinomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone 14.13-Z-[1-(4-guanidinomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone

Abbreviations used:

HOBt=1-hydroxy-1H-benzotriazoleTBTU=O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate

Preparation of the Starting Materials: EXAMPLE I Dimethyl2-(4-fluoro-2-nitrophenyl)malonate

With ice-cooling, 185 g of potassium tert-butoxide are added to asolution of 188 ml of dimethyl malonate in 970 ml ofN-methylpyrrolidone, and the mixture is stirred for 2 hours. Over aperiod of 30 minutes, 150 ml of 2,5-difluoronitrobenzene are addeddropwise to the resulting slurry, and the mixture is then stirred at 85°C. for 6 hours. The mixture is poured into 4 liters of ice-water and 250ml of concentrated hydrochloric acid and extracted with 2 liters ofethyl acetate. The organic phase is dried with sodium sulphate andconcentrated. The oily residue is triturated twice with water and thentaken up in 600 ml of ethyl acetate. The solution is dried with sodiumsulphate and concentrated to dryness. The resulting crude product isrecrystallized from 600 ml of ethyl acetate/hexane=2:8 and dried.

Yield: 222 g (59% of theory)

R_(f) value: 0.40 (silica gel, cyclohexane/ethyl acetate=5:1)

C₁₁H₁₀FNO₆

Mass spectrum: m/z=270 [M−H]⁻

The following compounds are prepared analogously to Example I:

-   (I.1) Diethyl 2-(4-bromo-2-nitrophenyl)malonate    from 2,5-dibromonitrobenzene and diethyl malonate

R_(f) value: 0.40 (silica gel, petroleum ether/ethyl acetate=5:1)

C₁₃H₁₄BrNO₆

Mass spectrum: m/z=359/361 [M]⁺

-   (I.2) Dimethyl 2-(4-cyano-2-nitrophenyl)malonate    from 4-chloro-3-nitrobenzonitrile and dimethyl malonate

R_(f) value: 0.50 (silica gel, methylene chloride/methanol=50:1)

C₁₂H₁₀N₂O₆

Mass spectrum: m/z=277 [M−H]⁻

EXAMPLE II Methyl 4-cyano-2-nitrophenylacetate

14.2 g of dimethyl 2-(4-cyano-2-nitrophenyl)malonate (starting materialI.2) are dissolved in 200 ml of dimethyl sulphoxide, and 4.5 g oflithium chloride and 1.0 ml of water are added. The solution is stirredat 100° C. for 3.5 hours, 300 ml of ice-water are then added and themixture is allowed to stand for 12 hours. The resulting precipitate isfiltered off with suction, taken up in methylene chloride and washedwith water. The organic phase is dried over sodium sulphate,concentrated using a rotary evaporator and dried.

Yield: 7.7 g (68% of theory)

R_(f) value: 0.40 (silica gel, methylene chloride/methanol)=50:1

C₁₀H₈N₂O₄

Mass spectrum: m/z=219 [M−H]⁻

EXAMPLE III 4-Fluoro-2-nitrophenylacetic Acid

At 100° C., 50.0 g of dimethyl 2-(4-fluoro-2-nitrophenyl)malonate(starting material I) are stirred in 400 ml of 6 molar hydrochloric acidfor 20 hours, 400 ml of water are then added and the mixture is cooledto 0° C. The resulting precipitate is filtered off with suction, washedwith water and 100 ml of petroleum ether and dried.

Yield: 34.5 g (94% of theory)

R_(f) value: 0.30 (silica gel, cyclohexane/ethyl acetate)=5:2

C₈H₆FNO₄

Mass spectrum: m/z=154 [M−COO−H]⁻

EXAMPLE IV 6-Fluoro-2-indolinone

With addition of 20 g of palladium on activated carbon (10%), 119 g of4-fluoro-2-nitrophenylacetic acid (starting material III) arehydrogenated in 600 ml of acetic acid under a hydrogen pressure of 50psi. The catalyst is filtered off with suction and the solvent isdistilled off. The crude product is triturated with 500 ml of petroleumether, filtered off with suction, washed with water and dried.

Yield: 82.5 g (91% of theory)

R_(f) value: 0.30 (silica gel, petroleum ether/ethyl acetate=1:1)

C₈H₆FNO

Mass spectrum: m/z=150 [M−H]⁻

The following compounds are prepared analogously to Example IV:

-   (IV.1) 6-Bromo-2-indolinone    from diethyl 2-(4-bromo-2-nitrophenyl)malonate (starting material    1.1) using Raney nickel as hydrogenation catalyst

R_(f) value: 0.45 (silica gel, petroleum ether/ethyl acetate=1:1)

C₈H₆BrNO

Mass spectrum: m/z=210/212 [M−H]⁻

-   (IV.2) 6-Cyano-2-indolinone    from methyl 4-cyano-2-nitrophenylacetate (starting material II)    using palladium/calcium carbonate as hydrogenation catalyst

R_(f) value: 0.45 (silica gel, methylene chloride/methanol=9:1)

C₉H₆N₂O

Mass spectrum: m/z=157 [M−H]⁻

EXAMPLE V 1-acetyl-6-fluoro-2-indolinone

At 130° C., 82.5 g of 6-fluoro-2-indolinone (starting material IV) arestirred in 180 ml acetic anhydride for 3 hours. After cooling to roomtemperature, the precipitate is filtered off with suction, washed with100 ml of petroleum ether and dried.

Yield: 64.8 g (61% of theory)

R_(f) value: 0.75 (silica gel, petroleum ether/ethyl acetate=1:1)

C₁₀H₈FNO₂

Mass spectrum: m/z=192 [M−H]⁻

The following compounds are prepared analogously to Example V:

-   (V.1) 1-acetyl-6-chloro-2-indolinone    from 6-chloro-2-indolinone and acetic anhydride

R_(f) value: 0.55 (silica gel, petroleum ether/ethyl acetate=2:3)

C₁₁H₁₀ClNO₆

Mass spectrum: m/z=208/210 [M−H]⁻

-   (V.2) 1-acetyl-6-bromo-2-indolinone    from 6-bromo-2-indolinone (starting material IV.1) and acetic    anhydride

R_(f) value: 0.60 (silica gel, petroleum ether/ethyl acetate=2:1)

C₁₀H₈BrNO₂

Mass spectrum: m/z=253/255 [M]⁺

-   (V.3) 1-acetyl-6-cyano-2-indolinone    from 6-cyano-2-indolinone (starting material IV.2) and acetic    anhydride

R_(f) value: 0.60 (silica gel, methylene chloride/methanol=50:1)

C₁₁H₈N₂O₂

Mass spectrum: m/z=199 [M−H]⁻

EXAMPLE VI1-acetyl-3-[1-hydroxy-1-(3-iodophenyl)methylene]-6-chloro-2-indolinone

10.5 g of 1-acetyl-6-chloro-2-indolinone (starting material V.1), 13.6 gof 3-iodobenzoic acid and 17.7 g of TBTU are initially charged in 100 mlof dimethylformamide, 35 ml of triethylamine are added and the mixtureis stirred at room temperature for 12 hours. After this time, thesolvent is removed under reduced pressure, water is added to the residueand the residue is filtered off with suction, washed with a littlewater, methanol and ether and dried at 100° C. under reduced pressure.

Yield: 12.9 g (59% of theory)

R_(f) value: 0.80 (silica gel, methylene chloride/methanol=9:1)

C₁₇H₁₁ClINO₃

Mass spectrum: m/z=438/440 [M−H]⁻

The following compounds are prepared analogously to Example VI:

-   (VI.1)    1-acetyl-3-[1-hydroxy-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone    from 1-acetyl-6-fluoro-2-indolinone (starting material V) and methyl    (4-carboxyphenyl)acetate (preparation according to Tetrahedron 1997,    53, 7335-7340)-   (VI.2)    1-acetyl-3-[1-hydroxy-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone    from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and    4-chlorobenzoic acid-   (VI.3)    1-acetyl-3-[1-hydroxy-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone    from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and    3,4-dimethoxybenzoic acid-   (VI.4)    1-acetyl-3-[1-hydroxy-1-(3,4-dimethoxyphenyl)methylene]-6-cyano-2-indolinone    from 1-acetyl-6-cyano-2-indolinone (starting material V.3) and    3,4-dimethoxybenzoic acid-   (VI.5)    1-acetyl-3-[1-hydroxy-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone    from 1-acetyl-6-fluoro-2-indolinone (starting material V) and    3-fluorobenzoic acid-   (VI.6)    1-acetyl-3-[1-hydroxy-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone    from 1-acetyl-6-fluoro-2-indolinone (starting material V) and    4-(2-acetylaminoethyl)-benzoic acid (preparation according to J. Am.    Chem. Soc. 1943, 65, 2377)-   (VI.7) 1-acetyl-3-[1-hydroxy-1-(3-methoxycarbonylmethyl    phenyl)methylene]-6-fluoro-2-indolinone    from 1-acetyl-6-fluoro-2-indolinone (starting material V) and methyl    (3-carboxyphenyl)acetate (preparation analogously to Tetrahedron    1997, 53, 7335-7340)-   (VI.8)    1-acetyl-3-[1-hydroxy-1-(3-(N-tert-butoxycarbonylaminomethyl)phenyl)-methylene]-6-fluoro-2-indolinone    from 1-acetyl-6-fluoro-2-indolinone (starting material V) and    3-(N-tert-butoxycarbonyl-aminomethyl)benzoic acid (preparation    according to Tetrahedron 1997, 53, 7335-7340)-   (VI.9)    1-acetyl-3-[1-hydroxy-1-(3-cyanomethylphenyl)methylene]-6-fluoro-2-indolinone    from 1-acetyl-6-fluoro-2-indolinone (starting material V) and    (3-carboxyphenyl)-acetonitrile (preparation according to J. Prakt.    Chem. 1998, 340, 367-374)-   (VI.10)    1-acetyl-3-[1-hydroxy-1-(4-(N-tert-butoxycarbonylaminomethyl)phenyl)-methylene]-6-fluoro-2-indolinone    from 1-acetyl-6-fluoro-2-indolinone (starting material V) and    4-(N-tert-butoxycarbonyl-aminomethyl)benzoic acid (preparation    according to Bioorg. Med. Chem. Lett 2000, 10, 553-557)-   (VI.11)    1-acetyl-3-[1-hydroxy-1-(4-iodophenyl)methylene]-6-fluoro-2-indolinone    from 1-acetyl-6-fluoro-2-indolinone (starting material V) and    4-iodobenzoic acid-   (VI.12)    1-acetyl-3-[1-hydroxy-1-(4-iodophenyl)methylene]-6-chloro-2-indolinone    from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and    4-iodobenzoic acid-   (VI.13)    1-acetyl-3-[1-hydroxy-1-(3-iodophenyl)methylene]-6-fluoro-2-indolinone    from 1-acetyl-6-fluoro-2-indolinone (starting material V) and    3-iodobenzoic acid-   (VI.14)    1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone    from 1-acetyl-6-fluoro-2-indolinone (starting material V) and    4-(2-methoxycarbonylethyl)benzoic acid (preparation analogously to    Tetrahedron 1997, 53, 7335-7340)-   (VI.15)    1-acetyl-3-[1-hydroxy-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone    from 1-acetyl-6-fluoro-2-indolinone (starting material V) and    3-(2-methoxycarbonylethyl)benzoic acid (preparation analogously to    Tetrahedron 1997, 53, 7335-7340)-   (VI.16)    1-acetyl-3-[1-hydroxy-1-(3-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone    from 1-acetyl-6-fluoro-2-indolinone (starting material V) and    3-(N-tert-butoxycarbonyl-2-aminoethyl)benzoic acid (preparation    analogously to Bioorg. Med. Chem. Lett 2000, 10, 553-557)-   (VI.17)    1-acetyl-3-[1-hydroxy-1-(4-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone    from 1-acetyl-6-fluoro-2-indolinone (starting material V) and    4-(N-tert-butoxycarbonyl-2-aminoethyl)benzoic acid (preparation    analogously to Bioorg. Med. Chem. Lett 2000, 10, 553-557)-   (VI.18)    1-acetyl-3-[1-hydroxy-1-(4-cyanophenyl)methylene]-6-chloro-2-indolinone    from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and    4-cyanobenzoic acid-   (VI.19)    1-acetyl-3-[1-hydroxy-1-(3-acetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone    from 1-acetyl-6-fluoro-2-indolinone (starting material V) and    3-acetylaminomethyl-benzoic acid (prepared according to J. Med.    Chem. 1997, 40, 4030-4052)-   (VI.20)    1-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone    from 1-acetyl-6-fluoro-2-indolinone (starting material V) and    3-(2-ethoxycarbonylethyl)benzoic acid (preparation analogously to    Tetrahedron 1997, 53, 7335-7340)-   (VI.21)    1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone    from 1-acetyl-6-chloro-2-indolinone (starting material V.1) and    4-(2-methoxycarbonylethyl)benzoic acid (preparation analogously to    Tetrahedron 1997, 53, 7335-7340)-   (VI.22)    1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone    from 1-acetyl-6-fluoro-2-indolinone (starting material V) and    4-(2-ethoxycarbonylethyl)benzoic acid (preparation analogously to    Tetrahedron 1997, 53, 7335-7340)-   (VI.23)    1-acetyl-3-[1-hydroxy-1-(3-methoxycarbonylmethyloxy-phenyl)methylene]-6-fluoro-2-indolinone    from 1-acetyl-6-fluoro-2-indolinone (starting material V) and    3-methoxycarbonylmethyloxybenzoic acid (preparation see Tetrahedron    Letters 1998, 39, 8563-8566)-   (VI.24)    1-acetyl-3-[1-hydroxy-1-(4-methoxycarbonylmethyloxyphenyl)methylene]-6-fluoro-2-indolinone    from 1-acetyl-6-fluoro-2-indolinone (starting material V) and    4-methoxycarbonylmethyloxybenzoic acid (preparation analogously to    Tetrahedron Letters 1998, 39, 8563-8566)-   (VI.25)    1-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone    from 1-acetyl-6-fluoro-2-indolinone (starting material V) and    3-(2-ethoxycarbonylethyloxy)benzoic acid (preparation see PCT Int.    Appl. WO9620173, 60)-   (VI.26)    1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone    from 1-acetyl-6-fluoro-2-indolinone (starting material V) and    4-(2-ethoxycarbonylethyloxy)benzoic acid (preparation see PCT Int.    Appl. WO9620173, 58)-   (VI.27)    1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone    from 1-acetyl-6-bromo-2-indolinone (starting material V.2) and    4-(2-methoxycarbonylethyl)-benzoic acid (preparation analogously to    Tetrahedron 1997, 53, 7335-7340)

EXAMPLE VII1-acetyl-3-[1-methoxy-1-(3-iodophenyl)methylene]-6-chloro-2-indolinone

A little at a time, 2.36 g of trimethyloxonium tetrafluoroborate areadded to a solution of 3.52 g of1-acetyl-3-[1-hydroxy-1-(3-iodophenyl)methylene]-6-chloro-2-indolinone(starting material VI) and 2.72 ml of ethyldiisopropylamine in 80 ml ofdichloromethane, and the mixture is stirred at room temperature for onehour. Another 1.4 ml of ethyldiisopropylamine and 1.2 g oftrimethyloxonium tetrafluoroborate are added, and the mixture is stirredat room temperature for another two hours. The mixture is then extractedwith water and the organic phase is dried over magnesium sulphate andevaporated to dryness. The residue is recrystallized from ether anddried at 80° C. under reduced pressure.

Yield: 2.40 g (66% of theory)

R_(f) value: 0.60 (silica gel, petroleum ether/dichloromethane/ethylacetate=5:4:1)

C₁₈H₁₃ClINO₃

Mass spectrum: m/z=438/440 [M−H]⁻

m.p. 185-187° C.

The following compounds are prepared analogously to Example VII:

-   (VII.1)    1-acetyl-3-[1-methoxy-1-(4-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone    from 1-acetyl-3-[1-hydroxy-1-(4-methoxycarbonylmethyl    phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.1)-   (VII.2)    1-acetyl-3-[1-methoxy-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(4-chlorophenyl)methylene]-6-chloro-2-indolinone    (starting material VI.2)-   (VII.3)    1-acetyl-3-[1-methoxy-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(3,4-dimethoxyphenyl)methylene]-6-chloro-2-indolinone    (starting material VI.3)-   (VII.4)    1-acetyl-3-[1-methoxy-1-(3,4-dimethoxyphenyl)methylene]-6-cyano-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(3,4-dimethoxyphenyl)-methylene]-6-cyano-2-indolinone    (starting material VI.4)-   (VII.5)    1-acetyl-3-[1-methoxy-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(3-fluorophenyl)methylene]-6-fluoro-2-indolinone    (starting material VI.5)-   (VII.6)    1-acetyl-3-[1-methoxy-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(4-(2-acetylaminoethyl)phenyl)methylene]-6-fluoro-2-indolinone    (starting material VI.6)-   (VII.7)    1-acetyl-3-[1-methoxy-1-(3-methoxycarbonylmethylphenyl)methylene]-6-fluoro-2-indolinone    from 1-acetyl-3-[1-hydroxy-1-(3-methoxycarbonylmethyl    phenyl)methylene]-6-fluoro-2-indolinone (starting material VI.7)-   (VII.8)    1-acetyl-3-[1-methoxy-1-(3-(N-tert-butoxycarbonylaminomethyl)phenyl)-methylene]-6-fluoro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(3-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone    (starting material VI.8)-   (VII.9)    1-acetyl-3-[1-methoxy-1-(3-cyanomethylphenyl)methylene]-6-fluoro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(3-cyanomethylphenyl)methylene]-6-fluoro-2-indolinone    (starting material VI.9)-   (VII.10)    1-acetyl-3-[1-methoxy-1-(4-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(4-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone    (starting material VI.10)-   (VII.11)    1-acetyl-3-[1-methoxy-1-(4-iodophenyl)methylene]-6-fluoro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(4-iodophenyl)methylene]-6-fluoro-2-indolinone    (starting material VI.11)-   (VII.12)    1-acetyl-3-[1-methoxy-1-(4-iodophenyl)methylene]-6-chloro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(4-iodophenyl)methylene]-6-chloro-2-indolinone    (starting material VI.12)-   (VII.13)    1-acetyl-3-[1-methoxy-1-(3-iodophenyl)methylene]-6-fluoro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(3-iodophenyl)methylene]-6-fluoro-2-indolinone    (starting material VI.13)-   (VII.14)    1-acetyl-3-[1-methoxy-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone    (starting material VI.14)-   (VII.15)    1-acetyl-3-[1-methoxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone    (starting material VI.15)-   (VII.16)    1-acetyl-3-[1-methoxy-1-(4-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(4-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone    (starting material VI.17)-   (VII.17)    1-acetyl-3-[1-methoxy-1-(3-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(3-(N-tert-butoxycarbonyl-2-aminoethyl)phenyl)methylene]-6-fluoro-2-indolinone    (starting material VI.16)-   (VII.18)    1-acetyl-3-[1-methoxy-1-(3-acetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(3-acetylaminomethylphenyl)methylene]-6-fluoro-2-indolinone    (starting material VI.19)-   (VII.19)    1-acetyl-3-[1-methoxy-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone    (starting material VI.20)-   (VII.20)    1-acetyl-3-[1-methoxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone    (starting material VI.21)-   (VII.21)    1-acetyl-3-[1-methoxy-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyl)phenyl)methylene]-6-fluoro-2-indolinone    (starting material VI.22)-   (VII.22) 1-acetyl-3-[1-methoxy-1-(4-methoxycarbonyl    methyloxyphenyl)-methylene]-6-fluoro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(4-methoxycarbonylmethyloxyphenyl)methylene]-6-fluoro-2-indolinone    (starting material VI.23)-   (VII.23) 1-acetyl-3-[1-methoxy-1-(3-methoxycarbonyl    methyloxyphenyl)-methylene]-6-fluoro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(3-methoxycarbonylmethyloxyphenyl)methylene]-6-fluoro-2-indolinone    (starting material VI.24)-   (VII.24)    1-acetyl-3-[1-methoxy-1-(3-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(3-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone    (starting material VI.25)-   (VII.25)    1-acetyl-3-[1-methoxy-1-(4-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(4-(2-ethoxycarbonylethyloxy)phenyl)methylene]-6-fluoro-2-indolinone    (starting material VI.26)-   (VII.26)    1-acetyl-3-[1-methoxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone    from    1-acetyl-3-[1-hydroxy-1-(4-(2-methoxycarbonylethyl)phenyl)methylene]-6-bromo-2-indolinone    (starting material VI.27)

EXAMPLE VIII1-Acetyl-3-[1-chloro-1-(4-cyanophenyl)methylene]-6-chloro-2-indolinone

A suspension of 7.0 g of1-acetyl-3-[1-hydroxy-1-(4-cyanophenyl)methylene]-6-chloro-2-indolinone(starting material VI.18) and 6.39 g of phosphorus pentachloride in 150ml of dioxane is stirred at 100° C. for 6 hours. After addition of afurther 1.0 g of phosphorus pentachloride, the mixture is stirred at110° C. for another 4 hours. The solvent is then distilled off and theresidue is washed with ethyl acetate.

Yield: 4.5 g (61% of theory)

R_(f) value: 0.70 (silica gel, methylene chloride/methanol=50:1)

C₁₈H₁₀Cl₂N₂O₂

EXAMPLE IX

The syntheses of the following compounds have already been described inthe international application WO 01/27081:

-   (IX.1) 4-(diethylaminomethyl)aniline-   (IX.2) N-(2-dimethylaminoethyl)-N-methylsulphonyl-p-phenylenediamine-   (IX.3) 3-(dimethylaminomethyl)aniline-   (IX.4) 4-(dimethylaminomethyl)aniline-   (IX.5) 4-(2-dimethylaminoethyl)aniline-   (IX.6) 4-[N-(2-dimethylaminoethyl)-N-acetylamino]aniline-   (IX.7) 4-[N-(3-dimethylaminopropyl)-N-acetylamino]aniline-   (IX.8)    4-[(N-dimethylaminocarbonylmethyl-N-methylsulphonyl)amino]aniline-   (IX.9) N-(4-aminophenyl)-N-methylmethanesulphonamide-   (IX.10) N-(dimethylaminomethylcarbonyl)-N-methyl-p-phenylenediamine-   (IX.11)    N-[(2-dimethylaminoethyl)carbonyl]-N-methyl-p-phenylenediamine-   (IX.12) 4-(N-tert-butoxycarbonylaminomethyl)aniline-   (IX.13) 4-(N-ethyl-N-tert-butoxycarbonylaminomethyl)aniline-   (IX.14) 4-[(4-methylpiperazin-1-yl)methyl]aniline-   (IX.15) 4-(imidazol-1-ylmethyl)aniline-   (IX.16) 4-(1-methylimidazol-2-yl)aniline-   (IX.17) 4-[(N-(2-dimethylaminoethyl)-N-methylamino)methyl]aniline-   (IX.18) 4-(N-methyl-N-tert-butoxycarbonylaminomethyl)aniline-   (IX.19)    N-[(4-methylpiperazin-1-yl)methylcarbonyl]-N-methyl-p-phenylenediamine-   (IX.20) 4-(4-tert-butoxycarbonylpiperazin-1-ylmethyl)aniline-   (IX.21) 4-(thiomorpholin-4-ylmethyl)aniline-   (IX.22) 4-(pyrrolidin-1-ylmethyl)aniline-   (IX.23) 4-(morpholin-4-yl-methyl)aniline-   (IX.24) 4-(N-benzyl-N-methylaminomethyl)aniline-   (IX.25) 4-(N-ethyl-N-methylaminomethyl)aniline-   (IX.26) 4-[N-(2-dimethylaminoethyl)-N-methylamino]aniline-   (IX.27) 4-[(N-propyl-N-methylamino)methyl]aniline

The following compounds are prepared analogously to Example IX:

-   (IX.28) 4-[N-(2-(N-benzyl-N-methylamino)ethyl)-N-acetylamino]aniline-   (IX.29) 4-amino-N-(2-dimethylaminoethyl)-N-methylbenzamide-   (IX.30) 4-(4-methylpiperazin-1-ylcarbonyl)aniline-   (IX.31) 4-(2-dimethylaminoethoxy)aniline-   (IX.32) N-(4-dimethylaminobutylcarbonyl)-N-methyl-p-phenylenediamine-   (IX.33)    N-[(3-dimethylaminopropyl)carbonyl]-N-methyl-p-phenylenediamine

Preparation of the End Products: EXAMPLE 1.03-Z-[1-(4-(N-Methyl-N-methylsulphonylamino)anilino)-1-(3-iodophenyl)methylene]-6-chloro-2-indolinone

0.9 g of1-acetyl-3-(1-methoxy-1-(3-iodophenyl)methylene)-6-chloro-2-indolinone(starting material VII) and 0.5 g ofN-methyl-N-methylsulphonyl-p-phenylenediamine (starting material IX.9)are dissolved in 10 ml of dimethylformamide and stirred at 120° C. for 3hours. After cooling, 1.5 ml of piperidine are added and the mixture isstirred at room temperature for another hour. Water is added and theresulting precipitate is filtered off with suction, washed with a littlewater, methanol and ether and finally dried under reduced pressure at100° C.

Yield: 0.9 g (74% of theory),

R_(f) value: 0.6 (silica gel, methylene chloride/methanol=9:1)

m.p. 292-294° C.

C₂₃H₁₉ClIN₃O₃S

Mass spectrum: m/z=578/580 [M−H]⁻

The following compounds of the formula I-1 are prepared analogously toExample 1.0:

(I-1)

Start- Ex- ing am- mater- Empirical Mass m.p. R_(f) ple R³ R⁴, ialsformula spectrum [° C.] value* 1.1

—CH₂—NMe₂ VII IX.4 C₂₄H₂₁CllN₃O 529/531 [M + H]⁺ 238- 240 0.30 (A) 1.2

—N(Me)—(CO)— CH₂—NMe₂ VII.2 IX.10 C₂₆H₂₄Cl₂N₄O₂ 495/497 [M + H]⁺ 277-279 0.20 (B) 1.3

—N(COMe)— (CH₂)₂—NMe₂ VII.2 IX.6 C₂₇H₂₆Cl₂N₄O₂ 507/509 [M − H]⁻ 241- 2430.10 (B) 1.4

VII.2 IX.19 C₂₉H₂₉Cl₂N₅O₂ 548/550 [M − H]⁻ 266- 268 0.10 (B) 1.5

—N(COMe)— (CH₂)₃—NMe₂ VII.2 IX.7 C₂₈H₂₈Cl₂N₄O₂ 521/523 [M − H]⁻ 241- 2420.10 (B) 1.6

—CH₂—NMe₂ VII.2 IX.4 C₂₄H₂₁Cl₂N₃O 438/440 [M + H]⁺ 243- 244 0.10 (B) 1.7

—N(COMe)— (CH₂)₂—NMe₂ VII.3 IX.6 C₂₉H₃₁ClN₄O₄ 533/535 [M − H]⁻ 128- 1300.75 (C) 1.8

VII.3 IX.19 C₃₁H₃₄ClN₅O₄ 574/576 [M − H]⁻ 208- 210 0.65 (C) 1.9

—N(SO₂Me)— (CH₂)₂—NMe₂ VII.3 IX.2 C₂₈H₃₁ClN₄O₅S 569/571 [M − H]⁻ 198-200 0.75 (C) 1.10

—CH₂—NMe₂ VII.3 IX.4 C₂₆H₂₆ClN₃O₃ 462/464 [M − H]⁻ 239- 240 0.70 (C)1.11

VII.3 IX.29 C₂₉H₃₁ClN₄O₄ 533/535 [M − H]⁻ 147- 149 0.70 (C) *Eluentmixtures: (A): silica gel, methylene chloride/methanol 9:1 (B): silicagel, methylene chloride/ethanol 10:1 (C): silica gel, methylenechloride/methanol 4:1

EXAMPLE 2.03-Z-[1-(4-(Dimethylaminomethyl)anilino)-1-(4-cyanophenyl)methylene]-6-chloro-2-indolinone

1.07 g of1-acetyl-3-[1-chloro-1-(4-cyanophenyl)methylene]-6-chloro-2-indolinone(starting material VII) and 0.54 g of 4-(dimethylaminomethyl)aniline(starting material IX.4) are dissolved in 10 ml of dimethylformamide andstirred at 80° C. for 3 hours. After cooling, 1 ml of 6N aqueous sodiumhydroxide is added, and the mixture is stirred at room temperature for30 minutes. Water is added and the mixture is extracted three times withmethylene chloride. The combined organic phases are washed twice withwater, dried over sodium sulphate and concentrated using a rotaryevaporator, and the product is recrystallized from diethyl ether.

Yield: 0.92 g (72% of theory),

R_(f) value: 0.1 (silica gel, methylene chloride/methanol=9:1)

C₂₅H₂₁ClN₄O

Mass spectrum: m/z=427/429 [M−H]⁻

EXAMPLE 3.03-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(4-iodophenyl)methylene]-6-fluoro-2-indolinone

3.5 g of1-acetyl-3-(1-methoxy-1-(4-iodophenyl)methylene)-6-fluoro-2-indolinone(starting material VII.11) and 1.6 g of 4-(dimethylaminomethyl)aniline(starting material IX.4) are dissolved in 30 ml of dimethylformamide andstirred at 120° C. for 2 hours. After cooling, the solvent is removedunder reduced pressure, the residue is taken up in 30 ml of methanol and2 spatula tips of sodium methoxide are added. Once a yellow precipitatehas formed, this is filtered off with suction from the solvent and theresidue is washed with a little methanol and ether and finally driedunder reduced pressure at 100° C.

Yield: 1.9 g (46% of theory),

R_(f) value: 0.3 (silica gel, methylene chloride/methanol=9:1)

m.p. 243-246° C.

C₂₄H₂₁FIN₃O

Mass spectrum: m/z=514 [M+H]⁺

The following compounds of the formula I-3a are prepared analogously toExample 3.0:

(I-3a)

Start- Ex- ing am- mater- Empirical Mass m.p. R_(f) ple R² R³ R⁴, ialsformula spectrum [° C.] value* 3.1 —F

—CH₂—NMe₂ VII.5 IX.4 C₂₄H₂₁F₂N₃O 404 [M − H]⁻ 225- 227 0.20 (A) 3.2 —F

—N(COMe)— (CH₂)₃—NMe₂ VII.5 IX.7 C₂₈H₂₈F₂N₄O₂ 491 [M + H]⁺ 160- 163 0.20(A) 3.3 —F

VII.5 IX.19 C₂₉H₂₉F₂N₅O₂ 518 [M + H]⁺ 218- 220 0.40 (A) 3.4 —F

—CH₂—NMe₂ VII.6 IX.4 C₂₈H₂₉FN₄O₂ 471 [M − H]⁻ 106- 110 0.25 (A) 3.5 —F

—N(COMe)— (CH₂)₃—NMe₂ VII.6 IX.7 C₃₂H₃₆FN₅O₃ 558 [M + H]⁺ 194- 196 0.25(A) 3.6 —F

VII.6 IX.19 C₃₃H₃₇FN₆O₃ 583 [M − H]⁻ 238- 240 0.25 (A) 3.7 —F

—CH₂—NMe₂ VII.1 IX.4 C₂₇H₂₆FN₃O₃ 460 [M + H]⁺ 173- 176 0.30 (A) 3.8 —F

—CH₂—NMe₂ VII.13 IX.4 C₂₄H₂₁FlN₃O 514 [M + H]⁺ 198- 200 0.30 (B) 3.9 —F

—CH₂—NMe₂ VII.7 IX.4 C₂₇H₂₆FN₃O₃ 458 [M − H]⁻ 195- 198 0.25 (A) 3.10 —F

—CH₂—NMe₂ VII.8 IX.4 C₃₀H₃₃FN₄O₃ 517 [M + H]⁺ 230- 240 0.30 (A) 3.11 —F

—N(SO₂Me)— (CH₂)₂—NMe₂ VII.1 IX.2 C₂₉H₃₁FN₄O₅S 567 [M + H]⁺ 188- 1890.40 (A) 3.12 —F

VII.1 IX.19 C₃₂H₃₄FN₅O₄ 572 [M + H]⁺ 200- 203 0.35 (C) 3.13 —F

—CH₂—NMe₂ VII.9 IX.4 C₂₆H₂₃FN₄O 427 [M + H]⁺ 130- 135 0.25 (A) 3.14 —F

VII.10 IX.19 C₃₅H₄₁FN₆O₄ 629 [M + H]⁺ 215- 220 0.35 (A) 3.15 —F

—CH₂—NMe₂ VII.10 IX.4 C₃₀H₃₃FN₄O₃ 517 [M + H]⁺ 186- 190 0.35 (A) 3.16 —F

—CH₂—NMe₂ VII.17 IX.4 C₃₁H₃₅FN₄O₃ 531 [M + H]⁺ n.d. 0.40 (A) 3.17 —F

—NMe—(COMe) VII.15 — C₂₈H₂₆FN₃O₄ 488 [M + H]⁺ 166- 170 0.40 (A) 3.18 —F

VII.15 IX.19 C₃₃H₃₆FN₅O₄ 586 [M + H]⁺ 176- 180 0.30 (A) 3.19 —F

—N(SO₂Me)— (CH₂)₂—NMe₂ VII.15 IX.2 C₃₀H₃₃FN₄O₅S 581 [M + H]⁺ 195- 1980.45 (A) 3.20 —F

—N(COMe)— (CH₂)₃—NMe₂ VII.15 IX.7 C₃₂H₃₅FN₄O₄ 559 [M + H]⁺ 100- 104 0.50(A) 3.21 —F

VII.15 IX.18 C₃₂H₃₄FN₃O₅ 558 [M − H]⁻ 132- 137 0.80 (D) 3.22 —F

VII.15 IX.30 C₃₁H₃₁FN₄O₄ 543 [M + H]⁺ 234- 236 0.60 (A) 3.23 —F

VII.15 IX.16 C₂₉H₂₅FN₄O₃ 497 [M + H]⁺ 110- 115 0.40 (A) 3.24 —F

—SO₂Me VII.15 — C₂₆H₂₃FN₂O₅S 495 [M + H]⁺ 130- 137 0.60 (A) 3.25 —F

VII.7 IX.19 C₃₂H₃₄FN₅O₄ 572 [M + H]⁺ 189 0.60 (B) 3.26 —F

—N(SO₂Me)— (CH₂)₂—NMe₂ VII.7 IX.2 C₂₉H₃₁FN₄O₅S 567 [M + H]⁺ n.d. 0.60(B) 3.27 —F

VII.7 IX.30 C₃₀H₂₉FN₄O₄ 529 [M + H]⁺ 201- 203 0.60 (B) 3.28 —F

—N(Me)—(CO)— CH₂—NMe₂ VII.7 IX.10 C₂₉H₂₉FN₄O₄ 517 [M + H]⁺ 126 0.60 (B)3.29 —F

—N(COMe)— (CH₂)₂—NMe₂ VII.7 IX.6 C₃₀H₃₁FN₄O₄ 531 [M + H]⁺ 179 0.50 (B)3.30 —F

—N(COMe)— (CH₂)₃—NMe₂ VII.7 IX.7 C₃₁H₃₃FN₄O₄ 545 [M + H]⁺ 123 0.20 (B)3.31 —F

—N(Me)—(CO)— (CH₂)₄—NMe₂ VII.7 IX.32 C₃₂H₃₅FN₄O₄ 559 [M + H]⁺ 201 0.20(B) 3.32 —F

—H VII.1 — C₂₄H₁₉FN₂O₃ 403 [M + H]⁺ 198- 206 0.80 (A) 3.33 —F

VII.1 IX.16 C₂₈H₂₃FN₄O₃ 483 [M + H]⁺ 223- 226 0.75 (A) 3.34 —F

VII.1 IX.30 C₃₀H₂₉FN₄O₄ 529 [M + H]⁺ 215- 220 0.30 (A) 3.35 —F

—N(SO₂Me)— (CH₂)—(CO)— NMe₂ VII.1 IX.8 C₂₉H₂₉FN₄O₆S 581 [M + H]⁺ 227-230 0.65 (A) 3.36 —F

—N(Me)—(CO)— CH₂—NMe₂ VII.1 IX.10 C₂₉H₂₉FN₄O₄ 517 [M + H]⁺ 128- 130 0.45(A) 3.37 —F

—N(COMe)— CH₃ VII.1 — C₂₇H₂₄FN₃O₄ 474 [M + H]⁺ 218- 223 0.40 (A) 3.38 —F

—N(Me)—(CO)— (CH₂)₂—NMe₂ VII.1 IX.11 C₃₀H₃₁FN₄O₄ 531 [M + H]⁺ 192- 1940.40 (A) 3.39 —F

—SO₂Me VII.1 — C₂₅H₂₁FN₂O₅S 481 [M + H]⁺ 205- 214 0.65 (A) 3.40 —F

—N(Me)—(CO)— (CH₂)₃—NMe₂ VII.1 IX.33 C₃₁H₃₃FN₄O₄ 545 [M + H]⁺ 190- 1930.15 (A) 3.41 —F

—N(COMe)— (CH₂)₃—NMe₂ VII.1 IX.7 C₃₁H₃₃FN₄O₄ 545 [M + H]⁺ 184- 188 0.50(A) 3.42 —F

—H VII.7 — C₂₄H₁₉FN₂O₃ 403 [M + H]⁺ 114 0.70 (B) 3.43 —F

—SO₂Me VII.7 — C₂₅H₂₁FN₂O₅S 481 [M + H]⁺ 129 0.60 (B) 3.44 —F

VII.7 IX.16 C₂₈H₂₃FN₄O₃ 483 [M + H]⁺ 125 0.60 (B) 3.45 —F

—N(SO₂Me)— (CH₂)—(CO)— NMe₂ VII.7 IX.8 C₂₉H₂₉FN₄O₆S 581 [M + H]⁺ 1630.60 (B) 3.46 —F

—N(Me)—(CO)— (CH₂)₃—NMe₂ VII.7 IX.33 C₃₁H₃₃FN₄O₄ 545 [M + H]⁺ 101 0.10(B) 3.47 —F

—N(Me)—(CO)— (CH₂)₂—NMe₂ VII.7 IX.11 C₃₀H₃₁FN₄O₄ 531 [M + H]⁺ 161 0.20(B) 3.48 —F

VII.14 IX.19 C₃₀H₃₁FN₄O₄ 586 [M + H]⁺ 181- 183 0.20 (B) 3.49 —F

—N(SO₂Me)— (CH₂)₂—NMe₂ VII.14 IX.2 C₃₀H₃₃FN₄O₅S 581 [M + H]⁺ 158- 1600.35 (B) 3.50 —F

—N(Me)—(CO)— CH₂—NMe₂ VII.14 IX.10 C₃₀H₃₁FN₄O₄ 531 [M + H]⁺ n.d. 0.40(B) 3.51 —F

—N(COMe)— (CH₂)₃—NMe₂ VII.14 IX.7 C₃₂H₃₅FN₄O₄ 559 [M + H]⁺ n.d. 0.50 (E)3.52 —F

VII.8 IX.19 C₃₅H₄₁FN₆O₄ 629 [M + H]⁺ n.d. 0.35 (A) 3.53 —F

—NMe—(CO)— CH₃ VII.26 — C₂₇H₂₅FN₄O₃ 473 [M + H]⁺ 122- 126 0.50 (F) 3.54—F

—N(COMe)— (CH₂)₃—NMe₂ VII.26 IX.7 C₃₁H₃₄FN₅O₃ 544 [M + H]⁺ 80- 83 0.25(A) 3.55 —F

—N(SO₂Me)— (CH₂)₂—NMe₂ VII.18 IX.2 C₂₉H₃₂FN₅O₄S 566 [M + H]⁺ 190- 1950.30 (A) 3.56 —F

—N(Me)—(CO)— CH₂—NMe₂ VII.18 IX.10 C₂₉H₃₀FN₅O₃ 516 [M + H]⁺ 238- 2410.30 (G) 3.57 —F

—(CH₂)₂—NMe₂ VII.15 IX.5 C₂₉H₃₀FN₃O₃ 488 [M + H]⁺ 205- 208 0.55 (G) 3.58—F

—N(Me)—(CO)— (CH₂)₂—NMe₂ VII.15 IX.11 C₃₁H₃₁FN₄O₄ 543 [M − H]⁻ 196- 2020.20 (A) 3.59 —F

—N(Me)—(CO)— CH₂—NMe₂ VII.15 IX.10 C₃₀H₃₁FN₄O₄ 531 [M + H]⁺ 177- 1820.30 (A) 3.60 —F

—(CH₂)₂—NMe₂ VII.19 IX.5 C₃₀H₃₂FN₃O₃ 500 [M − H]⁻ 100- 105 0.35 (B) 3.61—F

—N(COMe)— (CH₂)₂—NMe₂ VII.15 IX.6 C₃₁H₃₃FN₄O₄ 545 [M + H]⁺ 167- 169 0.40(A) 3.62 —F

—N(Me)—(CO)— (CH₂)₃—NMe₂ VII.19 IX.33 C₃₃H₃₇FN₄O₄ 571 [M − H]⁻ n.d. 0.35(A) 3.63 —F

—N(Me)—(CO)— (CH₂)₄—NMe₂ VII.19 IX.32 C₃₄H₃₉FN₄O₄ 585 [M − H]⁻ n.d. 0.40(A) 3.64 —F

VII.19 IX.16 C₃₀H₂₇FN₄O₃ 511 [M + H]⁺ 95- 105 0.25 (B) 3.65 —F

—N(Me)—(CO)— (CH₂)₄—NMe₂ VII.15 IX.32 C₃₃H₃₇FN₄O₄ 573 [M + H]⁺ 173- 1750.20 (A) 3.66 —F

—H VII.15 — C₂₅H₂₁FN₂O₃ 417 [M + H]⁺ 168- 174 0.65 (A) 3.67 —F

VII.15 IX.22 C₃₀H₃₀FN₃O₃ 500 [M + H]⁺ 168- 173 0.40 (B) 3.68 —F

—CH₂—NEt₂ VII.15 IX.1 C₃₀H₃₂FN₃O₃ 502 [M + H]⁺ n.d. 0.45 (B) 3.69 —F

VII.15 IX.12 C₃₁H₃₂FN₃O₅ 544 [M − H]⁻ n.d. 0.30 (G) 3.70 —F

—(CH₂)₂—NMe₂ VII.7 IX.5 C₂₈H₂₈FN₃O₃ 472 [M − H]⁻ 165- 170 0.25 (B) 3.71—F

—(CH₂)₂—NMe₂ VII.1 IX.5 C₂₈H₂₈FN₃O₃ 472 [M − H]⁻ 193- 197 0.25 (B) 3.72—F

—CH₂—NMe₂ VII.19 IX.4 C₂₉H₃₀FN₃O₃ 488 [M + H]⁺ 48- 52 0.45 (B) 3.73 —Cl

—(CH₂)₂—NMe₂ VII.20 IX.5 C₂₉H₃₀ClN₃O₃ 504/506 [M + H]⁺ 156- 160 0.30 (H)3.74 —Cl

VII.20 IX.16 C₂₉H₂₅ClN₄O₃ 513/515 [M + H]⁺ 110 0.40 (H) 3.75 —Cl

—CH₂—NMe₂ VII.20 IX.4 C₂₈H₂₈ClN₃O₃ 490/492 [M + H]⁺ 173- 175 0.70 (I)3.76 —F

—CH₂—NMe₂ VII.21 IX.4 C₂₉H₃₀FN₃O₃ 488 [M + H]⁺ 158- 161 0.35 (B) 3.77 —F

VII.14 IX.14 C₃₁H₃₃FN₄O₃ 529 [M + H]⁺ 147- 150 0.50 (I) 3.78 —F

VII.14 IX.15 C₂₉H₂₅FN₄O₃ 497 [M + H]⁺ 182- 185 0.60 (K) 3.79 —F

VII.15 IX.14 C₃₁H₃₃FN₄O₃ 529 [M + H]⁺ 184 0.35 (B) 3.80 —F

VII.15 IX.15 C₂₉H₂₅FN₄O₃ 497 [M + H]⁺ 233 0.45 (B) 3.81 —F

—CH₂—NMe— (CH₂)₂—NMe₂ VII.15 IX.17 C₃₁H₃₅FN₄O₃ 531 [M + H]⁺ 120 0.40 (B)3.82 —F

—CH₂—NMe— (CH₂)₂—NMe₂ VII.19 IX.17 C₃₂H₃₇FN₄O₃ 545 [M + H]⁺ n.d. 0.40(K) 3.83 —Cl

VII.20 IX.22 C₃₀H₃₀ClN₃O₃ 516/518 [M + H]⁺ 195- 197 0.30 (H) 3.84 —F

—H VII.19 — C₂₆H₂₃FN₂O₃ 431 [M + H]⁺ 156- 160 0.80 (M) 3.85 —F

VII.19 IX.12 C₃₂H₃₄FN₃O₅ 560 [M + H]⁺ n.d. 0.50 (L) 3.86 —F

VII.19 IX.18 C₃₃H₃₆FN₃O₅ 574 [M + H]⁺ n.d. 0.60 (L) 3.87 —F

—CH₂—NMe₂ VII.22 IX.4 C₂₇H₂₆FN₃O₄ 476 [M + H]⁺ 129 0.25 (B) 3.88 —F

—CH₂—NMe₂ VII.23 IX.4 C₂₇H₂₆FN₃O₄ 476 [M + H]⁺ 155 0.25 (B) 3.89 —F

—CH₂—NMe₂ VII.24 IX.4 C₂₉H₃₀FN₃O₄ 504 [M + H]⁺ n.d. 0.20 (B) 3.90 —Br

VII.26 IX.22 C₃₀H₃₀BrN₃O₃ 560/562 [M + H]⁺ 230- 235 0.45 (B) 3.91 —Br

—CH₂—NMe₂ VII.26 IX.4 C₂₈H₂₈BrN₃O₃ 534/536 [M + H]⁺ 178- 180 0.35 (B)3.92 —Br

—CH₂—NEt₂ VII.26 IX.1 C₃₀H₃₂BrN₃O₃ 562/564 [M + H]⁺ 173- 176 0.40 (B)*Eluent mixtures: (A): silica gel, methylene chloride/methanol/ammonia9:1:0.1 (B): silica gel, methylene chloride/methanol 9:1 (C): silicagel, methylene chloride/methanol/ammonia 8:1:0.1 (D): silica gel,methylene chloride/methanol/ammonia 10:1:0.1 (E): silica gel, methylenechloride/methanol/ammonia 5:1:0.01 (F): silica gel, ethylacetate/methanol/ammonia = 9:1:0,1 (G): alumina, methylenechloride/methanol = 19:1 (H): silica gel, methylenechloride/methanol/ammonia 9:1:0.01 (I): silica gel, methylenechloride/methanol 5:1 (K): alumina, methylene chloride/ethanol = 20:1(L): silica gel, petroleum ether/ethyl acetate 1:1 (M): silica gel,petroleum ether/ethyl acetate 1:2

The following compounds of the formula I-3b are prepared analogously toExample 3.0:

(I-3b)

Start- Ex- ing am- mater- Empirical Mass m.p. R_(f) ple R² R³ R⁴, ialsformula spectrum [° C.] value* 3.93 —F

—CH₂—NMe₂ VII.15 IX.3 C₂₈H₂₈FN₃O₃ 474 [M + H]⁺ 176- 179 0.40 (A) 3.94 —F

—CH₂—NMe₂ VII.19 IX.3 C₂₉H₃₀FN₃O₃ 486 [M − H]⁻ n.d. 0.45 (B) 3.95 —Cl

—CH₂—NMe₂ VII.20 IX.3 C₂₈H₂₈ClN₃O₃ 490/492 [M + H]⁺ 163- 165 0.40 (A)*Eluent mixtures: (A): silica gel, methylene chloride/methanol 9:1 (B):silica gel, methylene chloride/methanol/ammonia 9:1:0.1

EXAMPLE 4.03-Z-[1-(4-(Dimethylaminomethyl)anilino)-1-(3,4-dimethoxyphenyl)methylene]-6-cyano-2-indolinone

130 mg of1-acetyl-3-(1-methoxy-1-(3,4-dimethoxyphenyl)methylene)-6-cyano-2-indolinone(starting material VII.4) and 58 mg of 4-(dimethylaminomethyl)aniline(starting material IX.4) are dissolved in 5 ml of dimethylformamide andstirred at 80° C. for 2 hours. After cooling, the solvent is removedunder reduced pressure and the residue is purified on a silica gelcolumn using the mobile phase methylene chloride/methanol 9:1.

Yield: 21 mg (12% of theory),

R_(f) value: 0.35 (silica gel, methylene chloride/methanol=9:1)

m.p. 265° C.

C₂₇H₂₆N₄O₃

EXAMPLE 5.03-Z-[1-(4-(N-Methyl-N-methylsulphonylamino)anilino)-1-(3-(2-methoxycarbonyl-vinyl)phenyl)methylene]-6-chloro-2-indolinone

580 mg of3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-iodophenyl)-methylene]-6-chloro-2-indolinone(starting material 1.0) and 140 ml of methyl acrylate are dissolved in20 ml of acetonitrile and 11 ml of dimethylformamide, and 11 mg ofpalladium(II) acetate, 2 ml of triethylamine and 30 mg oftri-ortho-tolylphosphine are added. Under nitrogen as protective gas,the solution is stirred at 90° C. for 10 hours. After cooling, thesolution is filtered through Celite, the solvent is removed underreduced pressure and the residue is purified on a silica gel columnusing the mobile phase methylene chloride/methanol 20:1.

Yield: 450 mg (84% of theory),

R_(f) value: 0.30 (silica gel, toluene/ethyl acetate=1:1)

m.p. 228-232° C.

C₂₇H₂₄ClN₃O₅S

Mass spectrum: m/z=537/539 [M]⁺

The following compounds of the formula I-5 are prepared analogously toExample 5.0:

(I-5)

Start- Ex- ing am- mater- Empirical Mass m.p. R_(f−) ple R² R³ R⁴, ialsformula spectrum [° C.] value* 5.1 —Cl

—CH₂—NMe₂ 1.1 C₂₈H₂₆ClN₃O₃ 486/488 [M − H]⁻ 150- 155 0.50 (A) 5.2 —F

—CH₂—NMe₂ 3.0 C₂₇H₂₅FN₄O₂ 455 [M − H]⁻ 269- 270 0.20 (B) 5.3 —F

—CH₂—NMe₂ 3.0 C₂₈H₂₆FN₃O₃ 470 [M − H]⁻ 205- 208 0.65 (A) 5.4 —F

—CH₂—NMe₂ 1.1 C₂₈H₂₆FN₃O₃ 472 [M + H]⁺ 138- 140 0.45 (A) *Eluentmixtures: (A): silica gel, methylene chloride/methanol 5:1 (B): silicagel, methylene chloride/methanol/ammonia 9:1:0.01

EXAMPLE 6.03-Z-[1-(4-Dimethylaminomethylanilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone

1.0 g of3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(2-methoxycarbonyl-vinyl)phenyl)methylene]-6-chloro-2-indolinone(starting material 5.1) is dissolved in 100 ml of methanol, and 200 mgof 10 percent palladium/carbon as catalyst are added. The mixture isthen hydrogenated at room temperature and a hydrogen pressure of 50 psifor 6 hours. After the reaction has ended, the catalyst is filtered off,the solvent is removed under reduced pressure and the residue is driedunder reduced pressure at 100° C.

Yield: 900 mg (90% of theory),

R_(f) value: 0.40 (silica gel, methylene chloride/methanol=9:1)

m.p. 160° C.

C₂₈H₂₈ClN₃O₃

Mass spectrum: m/z=490/492 [M+H]⁺

The following compounds of the formula I-6 are prepared analogously toExample 6.0:

(I-6)

Start- Ex- ing am- mater- Empirical Mass m.p. R_(f) ple R² R³ R⁴, ialsformula spectrum [° C.] value* 6.1 —Cl

—N(Me)— SO₂Me 5.0 C₂₇H₂₆ClN₃O₅S 538/540 [M − H]⁻ 148- 150 0.50 (A) 6.2—F

—CH₂—NMe₂ 5.2 C₂₇H₂₇FN₄O₂ 459 [M + H]⁺ 150 0.70 (B) 6.3 —F

—CH₂—NMe₂ 5.3 C₂₈H₂₈FN₃O₃ 474 [M + H]⁺ 140 0.35 (A) 6.4 —F

—CH₂—NMe₂ 5.4 C₂₈H₂₈FN₃O₃ 474 [M + H]⁺ 140- 142 0.30 (A) *Eluentmixtures: (A): silica gel, methylene chloride/methanol 9:1 (B): silicagel, methylene chloride/methanol/ammonia 5:1:0.01

EXAMPLE 7.03-Z-[1-(4-Dimethylaminomethylanilino)-1-(4-aminomethylphenyl)methylene]-6-chloro-2-indolinone

900 mg of3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-cyanophenyl)methylene]-6-chloro-2-indolinone(starting material 2.0) are dissolved in 20 ml of methylene chloride and30 ml of methanolic ammonia and, as catalyst, 200 mg of Raney nickel areadded. The mixture is then hydrogenated at room temperature and ahydrogen pressure of 50 psi for 2 hours and 15 minutes. After thereaction has ended, the catalyst is filtered off, the solvent is removedunder reduced pressure and the residue is washed with a little methanoland diethyl ether. To liberate the base, the residue is taken up in 1Naqueous sodium hydroxide solution and extracted four times withmethylene chloride/methanol 9:1. The combined organic phases are washedwith water and dried over sodium sulphate. The product is washed with alittle diethyl ether and dried under reduced pressure.

Yield: 680 mg (75% of theory),

R_(f) value: 0.60 (silica gel, methylenechloride/methanol/ammonia=9:1:0.1)

m.p. 211-214° C.

C₂₅H₂₅ClN₄O

Mass spectrum: m/z=433/435 [M+H]⁺

EXAMPLE 8.03-Z-[1-(4-(N-((4-Methylpiperazin-1-yl)methylcarbonyl)-N-methylamino)anilino)-1-(4-aminomethylphenyl)methylene]-6-chloro-2-indolinone

1.39 g of1-acetyl-3-Z-[1-(4-(N-((4-methylpiperazin-1-yl)methylcarbonyl)-N-methylamino)anilino)-1-(4-cyanophenyl)methylene]-6-chloro-2-indolinoneare dissolved in 20 ml of methylene chloride and 30 ml of methanolicammonia and, as catalyst, 200 mg of Raney nickel are added. The mixtureis then hydrogenated at room temperature at a hydrogen pressure of 50psi for 2 hours. After the reaction has ended, the catalyst is filtered,the solvent is removed under reduced pressure and the residue is washedwith a little methanol and diethyl ether. To liberate the base, theresidue is taken up in 1N aqueous sodium hydroxide solution andextracted four times with methylene chloride/methanol 9:1. The combinedorganic phases are washed with water and dried over sodium sulphate. Theproduct is purified on a silica gel column using, as mobile phase, agradient of methylene chloride and methylene chloride/methanol/ammonia8:1:0.1. The product is washed with a little diethyl ether and driedunder reduced pressure.

Yield: 700 mg (54% of theory),

R_(f) value: 0.15 (silica gel, methylenechloride/methanol/ammonia=9:1:0.1)

m.p. 232-235° C.

C₃₀H₃₃ClN₆O₂

Mass spectrum: m/z=544/546 [M]⁺

EXAMPLE 9.03-Z-[1-(4-(Dimethylaminomethyl)anilino)-1-(3-aminomethylphenyl)methylene]-6-fluoro-2-indolinone

2.72 g of3-Z-[1-(4-(dimethylaminomethyl)anilino)-1-(3-(N-tert-butoxycarbonyl-aminomethyl)phenyl)methylene]-6-fluoro-2-indolinone(starting material 3.10) are dissolved in 50 ml of methylene chloride,and 10 ml of trifluoroacetic acid are added. The mixture is stirred atroom temperature for 3 hours. After this time, most of the solvent isremoved under reduced pressure and the residue is taken up in ethylacetate and washed twice with 1N aqueous sodium hydroxide solution. Theorganic phase is dried over sodium sulphate, the solvent is removedusing a rotary evaporator and the residue is purified on a silica gelcolumn using the mobile phase methylene chloride/methanol/ammonia9:1:0.1. The product is washed with a little diethyl ether and driedunder reduced pressure.

Yield: 1.77 g (81% of theory),

R_(f) value: 0.25 (silica gel, methylene chloride/methanol/ammonia9:1:0.1)

m.p. 168-175° C.

C₂₅H₂₅FN₄O

Mass spectrum: m/z=415 [M−H]⁻

The following compounds of the formula I-9 are prepared analogously toExample 9.0:

(I-9)

Start- Ex- ing am- mater- Empirical Mass m.p. R_(f) ple R² R³ R⁴, ialsformula spectrum [° C.] value* 9.1 —F

—CH₂—NMe₂ 3.16 C₂₆H₂₇FN₄O 431 [M + H]⁺ 155- 160 0.45 (C) 9.2 —F

—CH₂—NMe₂ 3.15 C₂₅H₂₅FN₄O 417 [M + H]⁺ 203- 207 0.25 (A) 9.3 —F

3.14 C₃₀H₃₃FN₆O₂ 529 [M + H]⁺ 170- 175 0.15 (A) 9.4 —F

—CH₂—NHMe 10.11 C₂₆H₂₄FN₃O₃ 446 [M + H]⁺ 245- 251 0.20 (D) 9.5 —F

—CH₂—NHMe 11.22 C₂₆H₂₄FN₃O₃ 459 [M + H]⁺ 239- 243 0.30 (A) 9.6 —F

3.52 C₃₀H₃₃FN₆O₂ 529 [M + H]⁺ n.d. n.d. 9.7 —F

—CH₂—NH₂ 3.69 C₂₆H₂₄FN₃O₃ 444 [M − H]⁻ 158- 163 0.25 (A) 9.8 —F

—CH₂—NH₂ 3.85 C₂₇H₂₆FN₃O₃ 460 [M + H]⁺ 205- 210 0.30 (B) 9.9 —F

—CH₂—NHMe 3.86 C₂₈H₂₈FN₃O₃ 474 [M + H]⁺ 148- 150 0.30 (B) *Eluentmixtures: (A): silica gel, methylene chloride/methanol/ammonia 9:1:0.1(B): silica gel, methylene chloride/methanol/ammonia 9:1:0.01 (C):silica gel, methylene chloride/methanol/ammonia 8:2:0.2 (D): Reversedphase RP8, methanol/sodium chloride solution (5%) = 3:2

EXAMPLE 10.03-Z-[1-(4-Dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone

900 mg of3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-methoxycarbonylethyl)phenyl)methylene]-6-chloro-2-indolinone(starting material 6.0) are dissolved in 10 ml of ethanol, and 5 ml of1N aqueous sodium hydroxide solution are added. The mixture is stirredat room temperature for 5 hours. After cooling, 5 ml of 1N hydrochloricacid are added. The resulting precipitate is filtered off with suctionand washed with water.

Yield: 830 mg (95% of theory),

R_(f) value: 0.50 (reversed phase RP8, methanol/sodium chloride solution(5%)=4:1)

m.p. 210-215° C.

C₂₇H₂₆ClN₃O₃

Mass spectrum: m/z=476/478 [M+H]⁺

The following compounds of the formula I-10a are prepared analogously toExample 10.0:

(I-10a)

Start- Ex- ing am- mater- Empirical Mass m.p. R_(f) ple R² R³ R⁴, ialsformula spectrum [° C.] value* 10.1 —F

—CH₂—NMe₂ 6.3 C₂₇H₂₆FN₃O₃ 460 [M + H]⁺ 250 0.65 (A) 10.2 —F

—CH₂—NMe₂ 3.9 C₂₆H₂₄FN₃O₃ 444 [M − H]⁻ 278- 282 0.10 (B) 10.3 —F

—CH₂—NMe₂ 6.4 C₂₇H₂₆FN₃O₃ 458 [M − H]⁻ 198- 200 0.20 (C) 10.4 —F

—CH₂—NMe₂ 3.7 C₂₆H₂₄FN₃O₃ 444 [M − H]⁻ 212- 216 0.30 (D) 10.5 —F

3.12 C₃₁H₃₂FN₅O₄ 558 [M + H]⁺ 260- 263 0.20 (D) 10.6 —F

—N(SO₂Me)— (CH₂)₂—NMe₂ 3.11 C₂₈H₂₉FN₄O₅S 553 [M + H]⁺ 246- 249 0.30 (D)10.7 —F

—NMe—(CO)— CH₃ 3.17 C₂₇H₂₄FN₃O₄ 474 [M + H]⁺ 286- 290 0.60 (E) 10.8 —F

3.18 C₃₂H₃₄FN₅O₄ 570 [M − H]⁻ 215- 222 0.20 (D) 10.9 —F

—N(SO₂Me)— (CH₂)₂—NMe₂ 3.19 C₂₉H₃₁FN₄O₅S 567 [M + H]⁺ 160- 165 0.20 (D)10.10 —F

—N(COMe)— (CH₂)₃—NMe₂ 3.20 C₃₁H₃₃FN₄O₄ 545 [M + H]⁺ 153- 158 0.15 (D)10.11 —F

3.21 C₃₁H₃₂FN₃O₅ 546 [M + H]⁺ 215- 219 0.60 (E) 10.12 —F

3.22 C₃₀H₂₉FN₄O₄ 529 [M + H]⁺ 179- 186 0.25 (E) 10.13 —F

3.23 C₂₈H₂₃FN₄O₃ 483 [M + H]⁺ 264- 267 0.65 (E) 10.14 —F

—SO₂Me 3.24 C₂₅H₂₁FN₂O₅S 481 [M + H]⁺ 146- 155 0.70 (E) 10.15 —F

3.27 C₂₉H₂₇FN₄O₄ 515 [M + H]⁺ 251 0.70 (E) 10.16 —F

3.25 C₃₁H₃₂FN₅O₄ 558 [M + H]⁺ 234 0.10 (E) 10.17 —F

—N(Me)—(CO)— CH₂—NMe₂ 3.28 C₂₈H₂₇FN₄O₄ 503 [M + H]⁺ 203 0.60 (E) 10.18—F

—N(Me)—(CO)— (CH₂)₄—NMe₂ 3.31 C₃₁H₃₃FN₄O₄ 545 [M + H]⁺ 251 n.d. 10.19 —F

—H 3.42 C₂₃H₁₇FN₂O₃ 387 [M − H]⁻ 130 0.60 (E) 10.20 —F

—SO₂Me 3.43 C₂₄H₁₉FN₂O₅S 467 [M + H]⁺ 139 0.55 (E) 10.21 —F

3.44 C₂₇H₂₁FN₄O₃ 469 [M + H]⁺ 157 0.35 (E) 10.22 —F

—N(SO₂Me)— (CH₂)—(CO)— NMe₂ 3.45 C₂₈H₂₇FN₄O₆S 567 [M + H]⁺ 183 0.55 (E)10.23 —F

—H 3.32 C₂₃H₁₇FN₂O₃ 389 [M + H]⁺ 237- 240 0.10 (D) 10.24 —F

3.33 C₂₇H₂₁FN₄O₃ 469 [M + H]⁺ 259- 265 0.15 (D) 10.25 —F

—N(COMe)— (CH₂)₃—NMe₂ 3.41 C₃₀H₃₁FN₄O₄ 531 [M + H]⁺ 274- 278 0.15 (D)10.26 —F

—N(Me)—(CO)— CH₂—NMe₂ 3.36 C₂₈H₂₇FN₄O₄ 503 [M + H]⁺ 258- 264 0.20 (D)10.27 —F

3.34 C₂₉H₂₇FN₄O₄ 515 [M + H]⁺ 279- 282 0.15 (D) 10.28 —F

—SO₂Me 3.39 C₂₄H₁₉FN₂O₅S 467 [M + H]⁺ 260- 266 0.35 (F) 10.29 —F

—N(COMe)— CH₃ 3.37 C₂₆H₂₂FN₃O₄ 460 [M + H]⁺ 290- 294 0.30 (F) 10.30 —F

—N(SO₂Me)— CH₂—(CO)— NMe₂ 3.35 C₂₈H₂₇FN₄O₆S 567 [M + H]⁺ 238- 242 0.30(F) 10.31 —F

—N(Me)—(CO)— (CH₂)₂—NMe₂ 3.38 C₂₉H₂₉FN₄O₄ 517 [M + H]⁺ 250- 255 0.35 (F)10.32 —F

—N(Me)—(CO)— (CH₂)₃—NMe₂ 3.40 C₃₀H₃₁FN₄O₄ 531 [M + H]⁺ 184- 190 0.25 (F)10.33 —F

3.48 C₃₂H₃₄FN₅O₄ 572 [M − H]⁻ 170- 175 0.40 (C) 10.34 —F

—N(SO₂Me)— (CH₂)₂—NMe₂ 3.26 C₂₈H₂₉FN₄O₅S 553 [M + H]⁺ 180 0.60 (C) 10.35—F

—N(SO₂Me)— (CH₂)₂—NMe₂ 3.49 C₂₉H₃₁FN₄O₅S 567 [M + H]⁺ 196- 199 0.30 (C)10.36 —F

—N(Me)—(CO)— CH₂—NMe₂ 3.50 C₂₉H₂₉FN₄O₄ 517 [M + H]⁺ 150 0.20 (C) 10.37—F

—N(COMe)— (CH₂)₃—NMe₂ 3.51 C₃₁H₃₃FN₄O₄ 545 [M + H]⁺ 206- 210 0.30 (A)10.38 —F

—N(Me)—(CO)— CH₂—NMe₂ 3.59 C₂₉H₂₉FN₄O₄ 517 [M + H]⁺ 231- 236 0.60 (A)10.39 —F

—(CH₂)₂—NMe₂ 3.57 C₂₈H₂₈FN₃O₃ 474 [M + H]⁺ 218- 222 0.50 (A) 10.40 —F

—N(Me)—(CO)— (CH₂)₂—NMe₂ 3.58 C₃₀H₃₁FN₄O₄ 531 [M + H]⁺ 215- 218 0.50 (A)10.41 —F

—(CH₂)₂—NMe₂ 3.60 C₂₈H₂₈FN₃O₃ 474 [M + H]⁺ 172- 177 0.15 (G) 10.42 —F

—N(COMe)— (CH₂)₂—NMe₂ 3.61 C₃₀H₃₁FN₄O₄ 531 [M + H]⁺ 230- 234 0.50 (A)10.43 —F

—N(Me)—(CO)— (CH₂)₃—NMe₂ 3.62 C₃₁H₃₃FN₄O₄ 545 [M + H]⁺ 170- 175 0.30 (E)10.44 —F

—N(Me)—(CO)— (CH₂)₄—NMe₂ 3.63 C₃₂H₃₅FN₄O₄ 559 [M + H]⁺ 142- 146 0.10 (G)10.45 —F

3.64 C₂₈H₂₃FN₄O₃ 483 [M + H]⁺ 262- 269 0.20 (E) 10.46 —F

—N(Me)—(CO)— (CH₂)₄—NMe₂ 3.65 C₃₂H₃₅FN₄O₄ 559 [M + H]⁺ 234- 236 0.30 (A)10.47 —F

—H 3.66 C₂₄H₁₉FN₂O₃ 403 [M + H]⁺ 231- 233 0.20 (A) 10.48 —F

3.67 C₂₉H₂₈FN₃O₃ 486 [M + H]⁺ 205- 210 0.10 (E) 10.49 —F

—CH₂—NEt₂ 3.68 C₂₉H₃₀FN₃O₃ 488 [M + H]⁺ 145- 150 0.15 (E) 10.50 —F

—CH₂—NH₂ 9.7 C₂₅H₂₂FN₃O₃ 430 [M − H]⁻ 280- 285 0.05 (H) 10.51 —F

—(CH₂)₂—NMe₂ 3.70 C₂₇H₂₆FN₃O₃ 460 [M + H]⁺ 273- 276 0.15 (E) 10.52 —F

—(CH₂)₂—NMe₂ 3.71 C₂₇H₂₆FN₃O₃ 460 [M + H]⁺ 230- 235 0.05 (E) 10.53 —Cl

—(CH₂)₂—NMe₂ 3.73 C₂₈H₂₈ClN₃O₃ 490/492 [M + H]⁺ 255- 258 0.50 (A) 10.54—Cl

3.74 C₂₈H₂₃ClN₄O₃ 499/501 [M + H]⁺ 296- 300 0.50 (A) 10.55 —Cl

—CH₂—NMe₂ 3.75 C₂₇H₂₆ClN₃O₃ 476/478 [M + H]⁺ 228- 230 0.50 (A) 10.56 —F

3.77 C₃₀H₃₁FN₄O₃ 515 [M + H]⁺ 210- 215 0.40 (A) 10.57 —F

3.78 C₂₈H₂₃FN₄O₃ 483 [M + H]⁺ 240- 245 0.50 (A) 10.58 —F

—CH₂—NMe— (CH₂)₂—NMe₂ 3.82 C₃₀H₃₃FN₄O₃ 517 [M + H]⁺ n.d. 0.30 (I) 10.59—F

3.79 C₃₀H₃₁FN₄O₃ 515 [M + H]⁺ 275 0.35 (A) 10.60 —F

3.80 C₂₈H₂₃FN₄O₃ 483 [M + H]⁺ 280 0.55 (A) 10.61 —Cl

3.83 C₂₉H₂₈ClN₃O₃ 502/504 [M + H]⁺ 260- 266 0.50 (A) 10.62 —F

—CH₂—NMe— (CH₂)₂—NMe₂ 3.81 C₃₀H₃₃FN₄O₃ 517 [M + H]⁺ n.d. 0.05 (E) 10.63—F

—H 3.84 C₂₄H₁₉FN₂O₃ 403 [M + H]⁺ 110- 112 0.60 (K) 10.64 —F

—CH₂—NH₂ 9.8 C₂₅H₂₂FN₃O₃ 432 [M + H]⁺ 260- 263 0.60 (A) 10.65 —F

—CH₂—NHMe 9.9 C₂₆H₂₄FN₃O₃ 446 [M + H]⁺ 265- 270 0.60 (A) 10.66 —F

—CH₂—NMe₂ 3.87 C₂₆H₂₄FN₃O₄ 462 [M + H]⁺ 250 0.10 (M) 10.67 —F

—CH₂—NMe₂ 3.88 C₂₆H₂₄FN₃O₄ 462 [M + H]⁺ 247 0.15 (M) 10.68 —Br

3.90 C₂₉H₂₈BrN₃O₃ 546/548 [M + H]⁺ 290- 293 0.30 (E) 10.69 —Br

—CH₂—NMe₂ 3.91 C₂₇H₂₆BrN₃O₃ 520/522 [M + H]⁺ 243- 246 0.25 (E) 10.70 —Br

—CH₂—NEt₂ 3.92 C₂₉H₃₀BrN₃O₃ 548/550 [M + H]⁺ 252- 255 0.35 (E) *Eluentmixtures: (A): reversed phase RP8, methanol/sodium chloride solution(5%) = 4:1 (B): silica gel, methylene chloride/methanol = 8:2 (C):silica gel, methylene chloride/methanol = 5:1 (D): reversed phase RP8,methanol/sodium chloride solution (5%) = 3:2 (E): silica gel, methylenechloride/methanol = 9:1 (F): reversed phase RP8, methanol/sodiumchloride solution (5%) = 7:3 (G): silica gel, methylenechloride/methanol/ammonia = 9:1:0.1 (H): alumina, methylenechloride/methanol = 19:1 (I): reversed phase RP8, methanol/sodiumchloride solution (5%) = 4:2 (K): silica gel, petroleum ether/ethylacetate = 1:1 (M): silica gel, methylene chloride/methanol = 4:1

The following compounds of the formula I-10b are prepared analogously toExample 10.0:

(I-10b)

Starting Empirical Mass m.p. R_(f)- Example R² R³ R^(4′) materialsformula spectrum [° C.] value* 10.71 —F

—CH₂—NMe₂ 3.93 C₂₇H₂₆FN₃O₃ 460 [M + H]⁺ 150 0.20 (A) 10.72 —F

—CH₂—NMe₂ 3.94 C₂₇H₂₆FN₃O₃ 460 [M + H]⁺ 105- 109 0.30 (B) 10.73 —Cl

—CH₂—NMe₂ 3.95 C₂₇H₂₆ClN₃O₃ 476/478 [M + H]⁺ 230- 235 0.50 (C) *Eluentmixtures: (A): silica gel, methylene chloride/methanol = 5:1 (B): silicagel, methylene chloride/methanol = 9:1 (C): reversed phase RP8,methanol/sodium chloride solution (5%) = 4:1

EXAMPLE 11.03-Z-[1-(4-Dimethylaminomethylanilino)-1-(3-(2-carbamoylethyl)phenyl)methylene]-6-chloro-2-indolinone

480 mg of3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone(starting material 10.0), 350 mg of TBTU, 150 mg of HOBt and 420 ml oftriethylamine are dissolved in 10 ml of dimethylformamide, and 620 mg ofN-hydroxysuccinimide ammonium salt are added. The mixture is stirred atroom temperature for 20 hours. After removal of the solvent underreduced pressure, the residue is suspended in a little ethyl acetate andwater, filtered off and washed with water. The residue is purified on analumina column (activity 2-3) using the mobile phase methylenechloride/ethanol 20:1. The product is recrystallized from diethyl etherand dried under reduced pressure at 10° C.

Yield: 370 mg (78% of theory),

R_(f) value: 0.40 (alumina, methylene chloride/ethanol=20:1)

m.p. 222-225° C.

C₂₇H₂₇ClN₄O₂

Mass spectrum: m/z=475/477 [M+H]⁺

The following compounds of the formula I-11 are prepared analogously toExample 11.0:

(I-11)

Starting Empirical Mass m.p. R_(f) Example R² R³ R^(4′) materialsformula spectrum [° C.] value* 11.1 —Cl

—CH₂—NMe₂ 10.0 ** C₂₈H₂₉ClN₄O₂ 489/491 [M + H]⁺ 223- 225 0.50 (A) 11.2—F

—CH₂—NMe₂ 10.1 ** C₂₈H₂₉FN₄O₂ 473 [M + H]⁺ 148- 150 0.40 (B) 11.3 —F

—CH₂—NMe₂ 10.2 *** C₂₈H₂₉FN₄O₂ 473 [M + H]⁺  98- 103 0.30 (C) 11.4 —F

—CH₂—NMe₂ 10.3 C₂₇H₂₇FN₄O₂ 459 [M + H]⁺ 223- 225 0.50 (A) 11.5 —F

—CH₂—NMe₂ 10.3 ** C₂₈H₂₉FN₄O₂ 473 [M + H]⁺ 210- 213 0.70 (A) 11.6 —F

—CH₂—NMe₂ 10.3 *** C₂₉H₃₁FN₄O₂ 487 [M + H]⁺ 213- 215 0.80 (A) 11.7 —F

—CH₂—NMe₂ 10.2 C₂₆H₂₅FN₄O₂ 443 [M + H]⁺ 115- 120 0.25 (C) 11.8 —F

—CH₂—NMe₂ 10.2 ** C₂₇H₂₇FN₄O₂ 457 [M − H]⁻ 222- 225 0.25 (C) 11.9 —F

—CH₂—NMe₂ 10.4 C₂₆H₂₅FN₄O₂ 443 [M − H]⁻ 143- 146 0.40 (D) 11.10 —F

—CH₂—NMe₂ 10.1 *** C₂₉H₃₁FN₄O₂ 487 [M + H]⁺ 198- 200 0.60 (B) 11.11 —F

—CH₂—NMe₂ 10.1 **** C₃₂H₃₆FN₅O₂ 542 [M + H]⁺ 175 0.60 (B) 11.12 —F

10.5 C₃₁H₃₃FN₆O₃ 557 [M + H]⁺ 150- 156 0.40 (E) 11.13 —F

—N(SO₂Me)— (CH₂)₂—NMe₂ 10.6 C₂₈H₃₀FN₅O₄S 552 [M + H]⁺ 197- 199 0.50 (D)11.14 —F

—CH₂—NMe₂ 10.4 *** C₂₈H₂₉FN₄O₂ 473 [M + H]⁺ 147- 152 0.35 (D) 11.15 —F

—CH₂—NMe₂ 10.4 ** C₂₇H₂₇FN₄O₂ 459 [M + H]⁺ 208- 214 0.35 (D) 11.16 —F

—N(SO₂Me)— (CH₂)₂—NMe₂ 10.6 ** C₂₉H₃₂FN₅O₄S 566 [M + H]⁺ 218- 222 0.50(A) 11.17 —F

—N(SO₂Me)— (CH₂)₂—NMe₂ 10.6 *** C₃₀H₃₄FN₅O₄S 580 [M + H]⁺ 199- 205 0.40(C) 11.18 —F

10.5 ** C₃₂H₃₅FN₆O₃ 571 [M + H]⁺ 155- 160 0.20 (C) 11.19 —F

—N(Me)—(CO)— CH₃ 10.7 ** C₂₈H₂₇FN₄O₃ 487 [M + H]⁺ 137- 145 0.50 (C)11.20 —F

10.8 ** C₃₃H₃₇FN₆O₃ 585 [M + H]⁺ 211- 219 0.40 (C) 11.21 —F

—N(SO₂Me)— (CH₂)₂—NMe₂ 10.9 ** C₃₀H₃₄FN₅O₄S 578 [M − H]⁻ 192- 200 0.50(C) 11.22 —F

 10.11 ** C₃₂H₃₅FN₄O₄ 559 [M + H]⁺ 180- 187 0.50 (C) 11.23 —F

 10.13 ** C₂₉H₂₆FN₅O₂ 496 [M + H]⁺ 262- 266 0.40 (C) 11.24 —F

—SO₂Me  10.14 ** C₂₆H₂₄FN₃O₄S 494 [M + H]⁺ 180- 188 0.60 (C) 11.25 —F

 10.12 ** C₃₁H₃₂FN₅O₃ 542 [M + H]⁺ 226- 230 0.50 (C) 11.26 —F

 10.16 ** C₃₂H₃₅FN₆O₃ 571 [M + H]⁺ 213 0.10 (G) 11.27 —F

 10.15 ** C₃₀H₃₀FN₅O₃ 528 [M + H]⁺ 245 0.40 (G) *Eluent mixtures: (A):silica gel, methylene chloride/methanol/ammonia = 5:1:0.01 (B): alumina,methylene chloride/ethanol = 20:1 (C): silica gel, methylenechloride/methanol/ammonia = 9:1:0.1 (D): silica gel, methylenechloride/methanol/ammonia = 6:1:0.1 (E): silica gel, methylenechloride/methanol/ammonia = 5:1:0.1 (F): silica gel, methylenechloride/methanol/ammonia = 7:1:0.1 (G): silica gel, methylenechloride/methanol = 9:1 ** using methylammonium chloride as baseequivalent *** using dimethylammonium chloride as base equivalent ****using piperidine hydrochloride as base equivalent

EXAMPLE 12.03-Z-[1-(4-Dimethylaminomethylanilino)-1-(4-acetylaminomethylphenyl)methylene]-6-chloro-2-indolinone

100 mg of3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-aminomethylphenyl)-methylene]-6-chloro-2-indolinone(starting material 7.0) are dissolved in 5 ml of methylene chloride and5 ml of pyridine, and 20 μl of acetyl chloride are added at 0° C. Themixture is stirred at 0° C. for 10 minutes and at room temperature for afurther 4 hours. Another 20 μl of acetyl chloride are then added, andthe mixture is stirred at room temperature for 12 hours. After thistime, the solvent is removed under reduced pressure and the residue istaken up in methylene chloride and washed with water. The aqueous phaseis extracted twice with methylene chloride and the combined organicphases are dried over sodium sulphate. The solvent is removed using arotary evaporator and the residue is washed with ether.

Yield: 51 mg (47% of theory),

R_(f) value: 0.30 (silica gel, methylenechloride/methanol/ammonia=9:1:0.01)

m.p. 219-220° C.

C₂₇H₂₇ClN₄O₂

Mass spectrum: m/z=473/475 [M−H]⁻

The following compounds of the formula I-12 are prepared analogously toExample 12.0:

(I-12)

Starting Empirical Mass m.p. R_(f)- Example R² R³ R^(4′) materialsformula spectrum [° C.] value* 12.1 —Cl

8.0 C₃₂H₃₅ClN₆O₃ 585/587 [M− H]⁻ 252- 255 0.25 (B) 12.2 —Cl

—CH₂—NMe₂ 7.0 C₃₂H₂₉ClN₄O₂ 535/537 [M− H]⁻ 238 (de- comp.) 0.45 (B) 12.3—Cl

8.0 C₃₇H₃₇ClN₆O₃ 647/649 [M− H]⁻ 282- 284 0.40 (B) 12.4 —F

—CH₂—NMe₂ 9.0 C₂₇H₂₇FN₄O₂ 457 [M− H]⁻ 245- 250 0.40 (C) 12.5 —F

—CH₂—NMe₂ 9.0 C₂₈H₂₉FN₄O₂ 471 [M− H]⁻ 212- 214 0.35 (D) 12.6 —F

—CH₂—NMe₂ 9.0 C₃₂H₂₉FN₄O₂ 519 [M− H]⁻ 237- 240 0.40 (D) 12.7 —F

—CH₂—NMe₂ 9.0 C₃₃H₃₁FN₄O₂ 533 [M− H]⁻ 187- 190 0.30 (D) 12.8 —F

—CH₂—NMe₂ 9.1 C₂₈H₂₉FN₄O₂ 471 [M− H]⁻ 234- 237 0.30 (D) 12.9 —F

—CH₂—NMe₂ 9.1 C₃₃H₃₁FN₄O₂ 533 [M− H]⁻ 144- 150 0.45 (C) 12.10 —F

—CH₂—NMe₂ 9.1 C₂₉H₃₁FN₄O₂ 485 [M− H]⁻ 235- 237 0.25 (D) 12.11 —F

—CH₂—NMe₂ 9.1 C₃₄H₃₃FN₄O₂ 547 [M− H]⁻ 217- 220 0.30 (D) 12.12 —F

—CH₂—NMe₂ 9.2 C₂₇H₂₇FN₄O₂ 457 [M− H]⁻ 112- 120 0.25 (D) 12.13 —F

—CH₂—NMe₂ 9.2 C₂₈H₂₉FN₄O₂ 586 [M+ H]⁺ 176- 180 0.30 (D) 12.14 —F

—CH₂—NMe₂ 9.2 C₃₃H₃₁FN₄O₂ 535 [M+ H]⁺  80-  85 0.35 (D) 12.15 —F

9.3 C₃₂H₃₅FN₆O₃ 569 [M− H]⁻ 230- 235 0.35 (D) 12.16 —F

9.3 C₃₃H₃₇FN₆O₃ 583 [M− H]⁻ 205- 210 0.30 (D) 12.17 —F

9.3 C₃₈H₃₉FN₆O₃ 645 [M− H]⁻ 217- 220 0.35 (D) 12.18 —F

9.6 C₃₄H₃₇FN₆O₃ 597 [M+ H]⁺ 209- 212 0.30 (D) 12.19 —F

9.6 C₃₅H₃₉FN₆O₃ 611 [M+ H]⁺ 190- 193 0.30 (D) 12.20 —F

9.6 C₃₆H₃₅FN₇O₃ 634 [M+ H]⁺ 160- 163 0.30 (D) 12.21 —F

9.6 C₃₇H₄₃FN₆O₃ 639 [M+ H]⁺ 223- 227 0.30 (D) 12.22 —F

9.6 C₃₆H₃₆FN₇O₃ 634 [M+ H]⁺ 170- 175 0.25 (D) 12.23 —F

9.6 C₃₄H₃₉FN₆O₃ 599 [M+ H]⁺ 194- 196 0.20 (D) 12.24 —F

9.6 C₃₅H₄₁FN₆O₃ 613 [M+ H]⁺ 197- 200 0.70 (E) 12.25 —F

9.6 C₃₈H₄₅FN₆O₃ 653 [M+ H]⁺ 130- 135 0.75 (E) 12.26 —F

9.6 C₃₃H₃₇FN₆O₄ 601 [M+ H]⁺ 155- 159 0.60 (E) 12.27 —F

9.6 C₃₈H₃₉FN₆O₄ 663 [M+ H]⁺ 168- 172 0.35 (C) 12.28 —F

9.6 C₃₆H₄₃FN₆O₃ 627 [M+ H]⁺  85-  90 0.35 (C) 12.29 —F

9.6 C₃₅H₃₅FN₆O₃S 639 [M+ H]⁺ 170- 175 0.25 (C) 12.30 —F

9.6 C₃₅H₄₁FN₆O₃ 613 [M+ H]⁺ 242- 245 0.30 (C) 12.31 —F

9.6 C₃₅H₃₅FN₆O₄ 623 [M+ H]⁺ 155- 160 0.65 (F) 12.32 —F

9.6 C₃₅H₃₅FN₆O₄ 571 [M+ H]⁺ 190- 195 0.60 (F) 12.33 —F

9.6 C₃₂H₃₅FN₆O₃ 585 [M+ H]⁺ 203- 209 0.65 (E) 12.34 —F

9.6 C₃₇H₃₇FN₆O₃ 633 [M+ H]⁺ 145- 150 0.60 (F) 12.35 —F

9.6 C₃₈H₃₉FN₆O₃ 647 [M+ H]⁺ 148- 151 0.65 (F) 12.36 —F

—CH₂—NMe₂ 9.0 C₂₉H₂₉FN₄O₂ 485 [M+ H]⁺ 216- 220 0.35 (D) 12.37 —F

—CH₂—NMe₂ 9.0 C₃₀H₃₁FN₄O₂ 499 [M+ H]⁺ 214- 217 0.35 (D) 12.38 —F

—CH₂—NMe₂ 9.0 C₃₁H₂₈FN₅O₂ 522 [M+ H]⁺ 205- 210 0.35 (D) 12.39 —F

—CH₂—NMe₂ 9.0 C₃₂H₃₅FN₄O₂ 527 [M+ H]⁺ 235- 237 0.35 (D) 12.40 —F

—CH₂—NMe₂ 9.0 C₃₁H₂₈FN₅O₂ 520 [M− H]⁻ 135- 140 0.20 (D) 12.41 —F

—CH₂—NMe₂ 9.0 C₂₉H₃₁FN₄O₂ 487 [M+ H]⁺ 210- 215 0.20 (D) 12.42 —F

—CH₂—NMe₂ 9.0 C₃₀H₃₃FN₄O₂ 501 [M+ H]⁺ 202- 206 0.25 (D) 12.43 —F

—CH₂—NMe₂ 9.0 C₃₃H₃₇FN₄O₂ 541 [M+ H]⁺ 198- 203 0.35 (D) 12.44 —F

—CH₂—NMe₂ 9.0 C₂₈H₂₉FN₄O₃ 489 [M+ H]⁺ 173- 177 0.35 (D) 12.45 —F

—CH₂—NMe₂ 9.0 C₃₃H₃₁FN₄O₃ 549 [M− H]⁺ 202- 207 0.50 (C) 12.46 —F

—CH₂—NMe₂ 9.0 C₃₁H₃₅FN₄O₂ 513 [M− H]⁺ 203- 209 0.45 (C) 12.47 —F

—CH₂—NMe₂ 9.0 C₃₀H₂₇FN₄O₂S 527 [M+ H]⁺ 245- 250 0.35 (C) 12.48 —F

—CH₂—NMe₂ 9.0 C₃₀H₃₃FN₄O₂ 501 [M+ H]⁺ 248- 252 0.45 (C) 12.49 —F

—CH₂—NMe₂ 9.0 C₃₀H₂₇FN₄O₃ 511 [M+ H]⁺ 216- 219 0.30 (C) 12.50 —F

—CH₂—NMe₂ 9.0 C₃₁H₂₈FN₅O₂ 522 [M+ H]⁺ 167- 170 0.20 (D) *Eluentmixtures: (A): silica gel, methylene chloride/ethanol/ammonia =20:1:0.01 (B): silica gel, methylene chloride/methanol/ammonia =9:1:0.01 (C): alumina, methylene chloride/methanol = 19:1 (D): silicagel, methylene chloride/methanol/ammonia = 9:1:0.1 (E): silica gel,methylene chloride/methanol/ammonia = 8:2:0.2 (F): alumina, methylenechloride/methanol = 9:1

Alternatively, the following acylating agents were used:

benzoyl chloride, propionyl chloride, phenylacetyl chloride,cyclopropanecarbonyl chloride, cyclobutanecarbonyl chloride,pyridin-2-ylcarbonyl chloride, pyridin-3-ylcarbonyl chloride,pyridin-4-ylcarbonyl chloride, cyclohexylcarbonyl chloride, isobutyrylchloride, 3-methylbutyryl chloride, cyclohexylmethylcarbonyl chloride,methoxyacetyl chloride, 2-methoxybenzoyl chloride, tert-butylacetylchloride, thiophene-2-carbonyl chloride, pivaloyl chloride, 2-furoylchloride

EXAMPLE 13.03-Z-[1-(4-Trimethylammoniummethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinoneIodide

200 mg of3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone(starting material 10.1) are dissolved in 40 ml of acetone, and 250 mlof methyl iodide are added. The mixture is stirred at room temperaturefor 20 hours. After this time, the resulting residue is filtered offwith suction. The product is dried at 80° C. under reduced pressure.

Yield: 200 mg (83% of theory),

R_(f) value: 0.50 (reversed phase RP8, methanol/sodium chloride solution(5%)=4:1)

m.p. 210° C.

C₂₈H₂₉FN₃O₃I

Mass spectrum: m/z=474 [M+H]⁺

The following compound of the formula I-13 is prepared analogously toExample 13.0:

(I-13)

Starting Empirical Mass m.p. R_(f) Example R² R³ R^(4′) materialsformula spectrum [° C.] value* 13.1 —F

10.3 C₂₈H₂₉FN₃O₃I 474 [M + H]⁺ 150 0.50 (A) *Eluent mixture: (A):reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1

EXAMPLE 14.03-Z-[1-(4-Guanidinomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinoneIodide

170 mg of3-Z-[1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone(starting material 10.50) are dissolved in 20 ml of tetrahydrofuran, and390 mg of 3,5-dimethylpyrazole-1-carboxamidine nitrate and 330 ml ofdiethylisopropylamine are added. The mixture is stirred under reflux for10 hours. After this time, the solvent is concentrated, water is addedand the resulting residue is filtered off with suction. The product isdried at 80° C.

Yield: 150 mg (81% of theory),

R_(f) value: 0.40 (silica gel, methylene chloride/methanol/aceticacid=5:1:0.1)

m.p. 290° C.

C₂₆H₂₄FN₅O₃

Mass spectrum: m/z=474 [M+H]⁺

The following compound of the formula I-14 is prepared analogously toExample 14.0:

(I-14)

Starting Empirical Mass m.p. R_(f) Example R² R³ R^(4′) materialsformula spectrum [° C.] value* 14.1 —F

10.64 C₂₆H₂₄FN₅O₃ 474 [M + H]⁺ 305 0.70 (A) *Eluent mixture: (A):reversed phase RP8, methanol/sodium chloride solution (5%) = 4:1

EXAMPLE 15

Dry vial with 75 mg of active compound per 10 ml

Composition:

Active compound 75.0 mg Mannitol 50.0 mg Water for injection ad 10.0 ml

Preparation:

Active compound and mannitol were dissolved in water. After filling, theproduct is freeze-dried. The ready-to-use solution is obtained bydissolving the product in water for injection.

EXAMPLE 16

Dry vial with 35 mg of active compound per 2 ml

Composition:

Active compound 35.0 mg Mannitol 100.0 mg Water for injection ad 2.0 ml

Preparation:

Active compound and mannitol were dissolved in water. After filling, theproduct is freeze-dried. The ready-to-use solution is obtained bydissolving the product in water for injection.

EXAMPLE 17

Tablet with 50 mg of active compound

Composition:

(1) Active compound 50.0 mg (2) Lactose 98.0 mg (3) Maize starch 50.0 mg(4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate  2.0 mg 215.0mg 

Preparation:

(1), (2) and (3) are mixed and granulated using an aqueous solution of(4). (5) is added to the dried granules. From this mixture, biplanartablets having a facet on both sides and being partially scored on oneside are pressed.

Diameter of the tablets: 9 mm.

EXAMPLE 18

Tablet with 350 mg of active compound

Composition:

(1) Active compound 350.0 mg (2) Lactose 136.0 mg (3) Maize starch 80.0mg (4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4.0 mg 600.0mg

Preparation:

(1), (2) and (3) are mixed and granulated using an aqueous solution of(4). (5) is added to the dried granules. From this mixture, biplanartablets having a facet on both sides and being partially scored on oneside are pressed.

Diameter of the tablets: 12 mm.

EXAMPLE 19

Capsules with 50 mg of active compound

Composition:

(1) Active compound 50.0 mg (2) Maize starch, dried 58.0 mg (3) Lactose,powdered 50.0 mg (4) Magnesium stearate  2.0 mg 160.0 mg 

Preparation:

(1) is ground with (3). This ground material is, with vigorous mixing,added to the mixture of (2) and (4).

This powder mixture is, in a capsule filling machine, filled into hardgelatin capsules size 3.

EXAMPLE 20

Capsules with 350 mg of active compound

Composition:

(1) Active compound 350.0 mg (2) Maize starch, dried 46.0 mg (3)Lactose, powdered 30.0 mg (4) Magnesium stearate 4.0 mg 430.0 mg

Preparation:

(1) is ground with (3). This ground material is, with vigorous mixing,added to the mixture of (2) and (4).

This powder mixture is, in a capsule filling machine, filled into hardgelatin capsules size 0.

EXAMPLE 21

Suppositories with 100 mg of active compound

1 suppository contains: Active compound 100.0 mg Polyethylene glycol (MW1500) 600.0 mg Polyethylene glycol (MW 6000) 460.0 mg Polyethylenesorbitan monostearate 840.0 mg 2000.0 mg 

Preparation:

The polyethylene glycol is melted together with polyethylene sorbitanmonostearate. At 40° C., the ground active substance is homogeneouslydispersed in the melt. The melt is cooled to 38° C. and poured intoslightly pre-cooled suppository moulds.

Analogously to the examples above, it is possible to prepare thefollowing compounds:

-   (1)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (2)    3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (3)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (4)    3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (5)    3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (6)    3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (7)    3-Z-[1-(4-(3-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (8)    3-Z-[1-(4-ethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (9)    3-Z-[1-(4-methylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (10)    3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (11)    3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (12)    3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (13)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (14)    3-Z-[1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (15)    3-Z-[1-(3-(methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (16)    3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (17)    3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (18)    3-Z-[1-(4-(N-(dimethylamino-carbonylmethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (19)    3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (20)    3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (21)    3-Z-[1-(4-(N—(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (22)    3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (23)    3-Z-[1-(4-(N-(2-dimethylaminoethyl-carbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (24)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (25)    3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (26)    3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (27)    3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (28)    3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (29)    3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (30)    3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (31)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenylmethylene]-6-chloro-2-indolinone-   (32)    3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (33)    3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (34)    3-Z-[1-(4-(piperazin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (35)    3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (36)    3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (37)    3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (38)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (39)    3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (40)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (41)    3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (42)    3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (43)    3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (44)    3-Z-[1-(4-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (45)    3-Z-[1-(4-ethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (46)    3-Z-[1-(4-methylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (47)    3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (48)    3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (49)    3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (50)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (51)    3-Z-[1-(4-aminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (52)    3-Z-[1-(3-(dimethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (53)    3-Z-[1-(3-(methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (54)    3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (55)    3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (56)    3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (57)    3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (58)    3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (59)    3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (60)    3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (61)    3-Z-[1-(4-(N—(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (62)    3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (63)    3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (64)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (65)    3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (66)    3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (67)    3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (68)    3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (69)    3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (70)    3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (71)    3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (72)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenylmethylene]-6-chloro-2-indolinone-   (73)    3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (74)    3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (75)    3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (76)    3-Z-[1-(4-(piperazin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (77)    3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (78)    3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (79)    3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-chloro-2-indolinone-   (80)    3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (81)    3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (82)    3-Z-[1-(4-(3-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (83)    3-Z-[1-(4-ethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (84)    3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (85)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (86)    3-Z-[1-(3-(methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (87)    3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (88)    3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (89)    3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (90)    3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (91)    3-Z-[1-(4-(N—(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (92)    3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (93)    3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (94)    3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (95)    3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (96)    3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (97)    3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (98)    3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (99)    3-Z-[1-(4-(piperazin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (100)    3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (101)    3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (102)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (103)    3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (104)    3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (105)    3-Z-[1-(4-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (106)    3-Z-[1-(4-ethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (107)    3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (108)    3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (109)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (110)    3-Z-[1-(3-(methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (111)    3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (112)    3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (113)    3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (114)    3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (115)    3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (116)    3-Z-[1-(4-(N—(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (117)    3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (118)    3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (119)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (120)    3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (121)    3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (122)    3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (123)    3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (124)    3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (125)    3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (126)    3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (127)    3-Z-[1-(4-(piperazin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (128)    3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (129)    3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-fluoro-2-indolinone-   (130)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (131)    3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (132)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (133)    3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (134)    3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (135)    3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (136)    3-Z-[1-(4-(3-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (137)    3-Z-[1-(4-ethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (138)    3-Z-[1-(4-methylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (139)    3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (140)    3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (141)    3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (142)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (143)    3-Z-[1-(4-aminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (144)    3-Z-[1-(3-(dimethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (145)    3-Z-[1-(3-(methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (146)    3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (147)    3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (148)    3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (149)    3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (150)    3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (151)    3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (152)    3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (153)    3-Z-[1-(4-(N—(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (154)    3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (155)    3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (156)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (157)    3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (158)    3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (159)    3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (160)    3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (161)    3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (162)    3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (163)    3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (164)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(4-(2-carboxyethyl)-phenylmethylene]-6-bromo-2-indolinone-   (165)    3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (166)    3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (167)    3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (168)    3-Z-[1-(4-(piperazin-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (169)    3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (170)    3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (171)    3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(4-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (172)    3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (173)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (174)    3-Z-[1-(4-(N-(dimethylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (175)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (176)    3-Z-[1-(4-(N-(2-methylaminoethyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (177)    3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (178)    3-Z-[1-(4-(N-(3-methylaminopropyl)-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (179)    3-Z-[1-(4-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (180)    3-Z-[1-(4-ethylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (181)    3-Z-[1-(4-methylaminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (182)    3-Z-[1-(4-(N-(4-methylpiperazin-1-ylmethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (183)    3-Z-[1-(4-(4-methylpiperazin-1-ylcarbonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (184)    3-Z-[1-(4-(N-(3-dimethylaminopropyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (185)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-propylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (186)    3-Z-[1-(4-aminomethylanilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (187)    3-Z-[1-(3-(dimethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (188)    3-Z-[1-(3-(methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (189)    3-Z-[1-(3-(2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (190)    3-Z-[1-(3-(3-dimethylaminopropyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (191)    3-Z-[1-(4-(2-dimethylaminoethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (192)    3-Z-[1-(4-(N-(dimethylaminocarbonylmethyl)-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (193)    3-Z-[1-(4-(N-methyl-N-methylsulphonylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (194)    3-Z-[1-(4-(N-methyl-N-acetylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (195)    3-Z-[1-(4-(1-methylimidazol-2-yl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (196)    3-Z-[1-(4-(N—(N-(2-dimethylaminoethyl)-N-methylaminomethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (197)    3-Z-[1-(4-(2-diethylaminoethylsulphonyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (198)    3-Z-[1-(4-(N-(2-dimethylaminoethylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (199)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (200)    3-Z-[1-(4-(2-dimethylaminoethoxy)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (201)    3-Z-[1-(4-(N-(4-dimethylaminobutylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (202)    3-Z-[1-(4-(N-(3-dimethylaminopropylcarbonyl)-N-methylamino)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (203)    3-Z-[1-(4-(methylethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (204)    3-Z-[1-(4-(methylpropylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (205)    3-Z-[1-(4-(methylbenzylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (206)    3-Z-[1-(4-(diethylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (207)    3-Z-[1-(4-(N-(2-dimethylaminoethyl)-N-methylaminomethyl)anilino)-1-(3-(2-carboxyethyl)phenylmethylene]-6-bromo-2-indolinone-   (208)    3-Z-[1-(4-(pyrrolidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (209)    3-Z-[1-(4-(azetidin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (210)    3-Z-[1-(4-((4-methylpiperazin-1-yl)methyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (211)    3-Z-[1-(4-(piperazin-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (212)    3-Z-[1-(4-(morpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (213)    3-Z-[1-(4-(thiomorpholin-4-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (214)    3-Z-[1-(4-(imidazol-1-ylmethyl)anilino)-1-(3-(2-carboxyethyl)phenyl)methylene]-6-bromo-2-indolinone-   (215)    3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)-methylene]-6-fluoro-2-indolinone-   (216)    3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethylamino-phenyl)-methylene]-6-fluoro-2-indolinone-   (217)    3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(N-methyl-carboxymethylamino)phenyl)methylene]-6-fluoro-2-indolinone-   (218)    3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(N-methyl-carboxymethylamino)phenyl)methylene]-6-fluoro-2-indolinone-   (219)    3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethoxyphenyl)-methylene]-6-chloro-2-indolinone-   (220)    3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethoxyphenyl)-methylene]-6-chloro-2-indolinone-   (221)    3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)-methylene]-6-chloro-2-indolinone-   (222)    3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethylaminophenyl)-methylene]-6-chloro-2-indolinone-   (223)    3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(N-methyl-carboxymethylamino)phenyl)methylene]-6-chloro-2-indolinone-   (224)    3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(N-methyl-carboxymethylamino)phenyl)methylene]-6-chloro-2-indolinone-   (225)    3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethoxyphenyl)-methylene]-6-bromo-2-indolinone-   (226)    3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethoxyphenyl)-methylene]-6-bromo-2-indolinone-   (227)    3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-carboxymethylaminophenyl)-methylene]-6-bromo-2-indolinone-   (228)    3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-carboxymethylaminophenyl)-methylene]-6-bromo-2-indolinone-   (229)    3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(N-methyl-carboxymethylamino)phenyl)methylene]-6-bromo-2-indolinone-   (230)    3-Z-[1-(4-dimethylaminomethylanilino)-1-(3-(N-methyl-carboxymethylamino)phenyl)methylene]-6-bromo-2-indolinone

In the tables above,

Me is methyl,Et is ethyl,Pr is propyl,nPr is n-propyl,iPr is isopropyl,nBu is n-butyl,tBu is tert-butyl andBn is benzyl.

1-11. (canceled)
 12. A method for treating excessive or abnormal cellproliferation comprising administering a compound of the formula

in which X is an oxygen atom, R¹ is a hydrogen atom, R² is a fluorinechlorine or bromine atom or a cyano group, R³ is a phenyl group or aphenyl group which is monosubstituted by a fluorine, chlorine, bromineor iodine atom or by a C₁₋₃-alkoxy group, where the abovementionedunsubstituted and the monosubstituted phenyl groups may additionally besubstituted in the 3- or 4-position by a fluorine chlorine or bromineatom, by a cyano group, by a C₁₋₃-alkoxy or C₁₋₂-alkyl-carbonyl-aminogroup, by a cyano-C₁₋₃-alkyl, carboxy-C₁₋₃-alkyl, carboxy-C₁₋₄-alkoxy,carboxy-C₁₋₃-alkylamino, carboxy-C₁₋₃-alkyl-N—(C₁₋₃-alkyl)-amino,C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl, C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkoxy,C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkylamino,C₁₋₄-alkoxy-carbonyl-C₁₋₃-alkyl-N—(C₁₋₃-alkyl)-amino, amino-C₁₋₃-alkyl,aminocarbonyl-C₁₋₃-alkyl, (C₁₋₂-alkylamino)-carbonyl-C₁₋₃-alkyl,di-(C₁₋₂-alkyl)-aminocarbonyl-C₁₋₃-alkyl,(C₁₋₂-alkyl-carbonyl)-amino-C₁₋₃-alkyl,(C₁₋₄-alkoxy-carbonyl)-amino-C₁₋₃-alkyl,(C₃₋₆-alkyl-carbonyl)-amino-C₁₋₃-alkyl,(phenyl-carbonyl)-amino-C₁₋₃-alkyl,(C₃₋₆-cycloalkyl-carbonyl)-amino-C₁₋₃-alkyl,(C₃₋₆-cycloalkyl-C₁₋₃-alkyl-carbonyl)-amino-C₁₋₃-alkyl,(thiophen-2-yl-carbonyl)-amino-C₁₋₃-alkyl,(furan-2-yl-carbonyl)-amino-C₁₋₃-alkyl,(phenyl-C₁₋₃-alkyl-carbonyl)-amino-C₁₋₃-alkyl,(2-(C₁₋₄-alkoxy)-benzoyl-carbonyl)-amino-C₁₋₃-alkyl,(pyridin-2-yl-carbonyl)-amino-C₁₋₃-alkyl,(pyridin-3-yl-carbonyl)-amino-C₁₋₃-alkyl-,(pyridin-4-yl-carbonyl)-amino-C₁₋₃-alkyl- orC₁₋₃-alkyl-piperazin-1-yl-carbonyl-C₁₋₃-alkyl group, by acarboxy-C₂₋₃-alkenyl, aminocarbonyl-C₂₋₃-alkenyl,(C₁₋₃-alkylamino)-carbonyl-C₂₋₃-alkenyl,di-(C₁₋₃-alkyl)-amino-carbonyl-C₂₋₃-alkenyl orC₁₋₄-alkoxy-carbonyl-C₂₋₃-alkenyl group, where the substituents may beidentical or different, R⁴ is a phenyl group or a phenyl group which ismonosubstituted by a C₁₋₃-alkyl group which is terminally substituted byan amino, guanidino, mono- or di-(C₁₋₂-alkyl)-amino-,N-[ω-di-(C₁₋₃-alkyl)-amino-C₂₋₃-alkyl]-N—(C₁₋₃-alkyl)-amino,N-methyl-(C₃₋₄-alkyl)-amino, N—(C₁₋₃-alkyl)-N-benzylamino,N—(C₁₋₄-alkoxycarbonyl)-amino, N—(C₁₋₃-alkoxycarbonyl)-C₁₋₄-alkylamino,4-(C₁₋₃-alkyl)-piperazin-1-yl, imidazol-1-yl, pyrrolidin-1-yl,azetidin-1-yl, morpholin-4-yl, piperazin-1-yl, thiomorpholin-4-yl group,by a di-(C₁₋₃-alkyl)-amino-(C₁₋₃-alkyl)-sulphonyl,2-[di-(C₁₋₃-alkyl)-amino]-ethoxy,4-(C₁₋₃-alkyl)-piperazin-1-yl-carbonyl,{-[di-(C₁₋₃-alkyl)-amino]-1-(C₂₋₃-alkyl)}-N—(C₁₋₃-alkyl)-amino-carbonyl,1-(C₁₋₃-alkyl)imidazol-2-yl, (C₁₋₃-alkyl)-sulphonyl group, or by a groupof the formula

in which R⁷ is a C₁₋₂-alkyl, C₁₋₂-alkyl-carbonyl,di-(C₁₋₂-alkyl)-amino-carbonyl-C₁₋₃-alkyl or C₁₋₃-alkylsulphonyl groupand R⁸ is C₁₋₃-alkyl, ω-[di-(C₁₋₂-alkyl)-amino]-C₂₋₃-alkyl,ω-[mono-(C₁₋₂-alkyl)-amino]-C₂₋₃-alkyl group, or a(C₁₋₃-alkyl)-carbonyl, (C₄₋₆-alkyl)-carbonyl or carbonyl-(C₁₋₃-alkyl)group which is terminally substituted by a di-(C₁₋₂-alkyl)-amino,piperazin-1-yl or 4-(C₁₋₃-alkyl)-piperazin-1-yl group, where alldialkylamino groups present in the radical R⁴ may also be present inquaternized form, for example as an N-methyl-(N,N-dialkyl)-ammoniumgroup, where the counterion is preferably selected from the groupconsisting of iodide, chloride, bromide, methylsulphonate,para-toluenesulphonate and trifluoroacetate, R⁵ is a hydrogen atom andR⁶ is a hydrogen atom, where the abovementioned alkyl groups includelinear and branched alkyl groups in which additionally one to 3 hydrogenatoms may be replaced by fluorine atoms, where additionally a carboxyl,amino or imino group present may be substituted by an in vivo cleavableradical or may be present in the form of a prodrug radical, for examplein the form of a group which can be converted in vivo into a carboxylgroup or in the form of a group which can be converted in vivo into animino or amino group, or a salt thereof.
 13. A method for treatingexcessive or abnormal cell proliferation according to claim 1 comprisingadministering a compound of the formula I according to claim 1, in whichX, R¹, R³, R⁴, R⁵ and R⁶ are as defined in claim 1 and R² is a fluorineor chlorine atom, or a salt thereof.
 14. A method for treating excessiveor abnormal cell proliferation according to claim 1 comprisingadministering a physiologically acceptable salt of said compoundaccording to claim
 1. 15. A method for treating excessive or abnormalcell proliferation according to claim 13 comprising administering aphysiologically acceptable salt of said compound according to claim 13.